Apoptosis Inhibitors

ABSTRACT

The invention provides compounds that are inhibitors or covalent modifiers of succinate dehydrogenase subunit B (SDHB) and/or inhibitors of apoptosis, and pharmaceutically acceptable salts, hydrates and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof with an effective amount of the compound or composition.

INTRODUCTION

Physiological apoptosis plays an essential role in maintaininghomeostasis in multicellular organisms, and aberrant apoptosis is knownto be a major feature of many diseases. Excessive apoptosis is closelyrelated to ischemia-associated injury, immunodeficient diseases, andneurodegenerative diseases including Alzheimer's syndrome, Parkinson'ssyndrome, Huntington's syndrome, and amyotrophic lateral sclerosis(ALS). Apoptosis is regulated by two main pathways: the death receptorpathway and the mitochondrial apoptosis pathway. Upon recognition ofstimulus that initiate mitochondrial apoptosis, the decision of whetheror not to initiate apoptosis is determined via the complicatedregulation of pro- and anti-apoptotic Bcl-2 protein family members. BH-3only proteins (tBid, Bim, etc) trigger the conformational activation ofBax and/or Bak, which in turn translocate to the mitochondrial outermembrane and lead to changes in the permeability of the mitochondrialouter membrane. These changes enable the release of proapoptoticproteins such as cytochrome c and Smac to cytoplasm and thesepro-apoptotic factors results in the activation of caspases, andultimately cell death.

The great majority of research into apoptosis inhibitors has beenfocused on targeting caspases or proteins of the pro-apoptotic Bcl-2family. Blocking caspase activity can stop the final execution step ofapoptosis, but, by this stage, cells have already suffered considerabledamage. Indeed, the degree of stress endured by these cells wouldtypically induce other types of cell death such as necrosis. Thus, it isclear that the identification of drug targets that function upstream inapoptosis signaling would represent an attractive alternative totargeting caspases. Several small molecule and peptide inhibitors havebeen developed that target the upstream pro-apoptotic Bcl-2 familymembers Bax and Bid, and some of these have shown protective effects ina global brain ischemia model. However, all of these apoptosisinhibitors have only moderate potency, with EC₅₀ values above themicromolar level. Additionally, blocking a single pro-apoptotic Bcl-2protein may have only limited effects because other pro-apoptotic Bcl-2family proteins have complementary function.

Here, a new class of apoptosis inhibitors (TC09) that block cytochrome crelease was developed through a phenotype-based high-throughput screenand a detailed structure-activity relationship study. We optimized thecellular activity of TC09 series to the low nanomolar level, and usedcellular reversibility assays to demonstrate the covalent binding modefor the interaction of TC09 with the target protein. Our data indicatethat TC09 apoptosis inhibitors function as stabilizers of themitochondrial electron transport chain by targeting succinatedehydrogenase subunit B, and showed neuron protection effects in animalmodels.

Pyrimidinyl compounds are disclosed in WO2008/157003, US2009/163545,U.S. Pat. No. 3,149,109, US2005/80111, Eng, et al.; Drug Metabolism andDisposition; vol. 41; nb. 8; (2013); p. 1470-1479.

SUMMARY OF THE INVENTION

The invention provides sulfonyl and sulfinyl pyrimidinyl compounds foruse in a person in need thereof, or in the manufacture of a medicament,to modify succinate dehydrogenase subunit B (SDHB), inhibit apoptosis,insulate or protect cells, like dopaminergic neurons, from damage fromapoptotic insults or treat Parkinson's disease. In an aspect thecompound is of formula I:

wherein:R1 is an optionally substituted, optionally hetero-, optionally cyclicC1-C18 hydrocarbyl;R2 is an optionally substituted heteroatom, or an optionallysubstituted, optionally hetero-, optionally cyclic C1-C18 hydrocarbyl;R3 is an optionally substituted, optionally hetero-, cyclic C3-C18hydrocarbyl; andR4 is H or an optionally substituted heteroatom, or an optionallysubstituted, optionally hetero-, optionally cyclic C1-C18 hydrocarbyl;or a corresponding sulfinyl, or a stereoisomer, hydrate, salt or acetatethereof, wherein the corresponding sulfinyl is:

The invention includes embodiments of the compound, including thesulfonyl, corresponding sulfinyl, or a stereoisomer, hydrate, salt oracetate thereof, such as wherein

R1 is an optionally substituted, optionally hetero-, optionally cyclicC1-C18 alkyl, or an optionally substituted, optionally hetero-,optionally cyclic C2-C18 alkenyl or alkynyl, or an optionallysubstituted, optionally hetero-, optionally cyclic C2-C18 aryl;

R1 is an optionally substituted, optionally hetero-, C1-C18 alky;R1 is an optionally substituted C1-C4 alky; or

R1 is Me or Et;

R2 is an optionally substituted, optionally hetero-, optionally cyclicC1-C18 alkyl, or an optionally substituted, optionally hetero-,optionally cyclic C2-C18 alkenyl or alkynyl, or an optionallysubstituted, optionally hetero-, optionally cyclic C2-C18 aryl;

R2 is an optionally substituted C1-C4 alkyl, alkenyl or alkynyl;R2 is an optionally substituted, optionally hetero-, cyclic C5-C6 alkyl,alkenyl or alkynyl;R2 is an amine, halide or azido;

R2 is F, CH2F, CHF2, or CF3; or R2 is CF3;

R3 is an optionally substituted, heterocyclic C3-C18 hydrocarbyl;R3 is an optionally substituted, optionally hetero-, C5-C18 or C5-C6aryl;R3 is an optionally substituted, heterocyclic, C5-C18 or C5-C6 aryl;R3 is an optionally substituted, N-heterocyclic, C3-C18 hydrocarbyl;R3 is an optionally substituted, N-heterocyclic, C5-C18 or C5-C6 aryl;R3 is an optionally substituted pyridinyl, pyrrolyl or pyrazolyl;R3 is an optionally substituted phenyl or thiophene; orR3 is an optionally substituted 5-pyridin-2(1H)-one;

R4 is H or an optionally substituted, optionally hetero-, optionallycyclic C1-C18 alkyl, or an optionally substituted, optionally hetero-,optionally cyclic C2-C18 alkenyl or alkynyl, or an optionallysubstituted, optionally hetero-, optionally cyclic C2-C18 aryl;

R4 is an optionally substituted C1-C4 alkyl, alkenyl or alkynyl;R4 is an optionally substituted, optionally hetero-, cyclic C5-C6 alkyl,alkenyl or alkynyl;R4 is H, amine, halide or azido; or

R4 is H;

and/or R3 is an optionally substituted 5-pyridin-2(1H)-one, of formulaII:

wherein:R5 is an optionally substituted, optionally hetero-, optionally cyclicC3-C18 hydrocarbyl;R5 is optionally substituted benzyl; orR5 is 3,4-dimethoxybenzyl.

In another aspect the invention provides sulfonyl pyrimidinyl compoundof formula I:

wherein:R1 is an optionally substituted, optionally hetero-, optionally cyclicC1-C18 hydrocarbyl;R2 is an optionally substituted heteroatom, or an optionallysubstituted, optionally hetero-, optionally cyclic C1-C18 hydrocarbyl;R3 is an optionally substituted, N-heterocyclic C3-C18 hydrocarbyl; andR4 is H or an optionally substituted heteroatom, or an optionallysubstituted, optionally hetero-, optionally cyclic C1-C18 hydrocarbyl;or a corresponding sulfinyl, or a stereoisomer, hydrate, salt or acetatethereof.

The invention includes embodiments of the compound, including thesulfonyl, corresponding sulfinyl, or a stereoisomer, hydrate, salt oracetate thereof, such as wherein

R1 is an optionally substituted, optionally hetero-, optionally cyclicC1-C18 alkyl, or an optionally substituted, optionally hetero-,optionally cyclic C2-C18 alkenyl or alkynyl, or an optionallysubstituted, optionally hetero-, optionally cyclic C2-C18 aryl;

R1 is an optionally substituted, optionally hetero-, C1-C18 alky;R1 is an optionally substituted C1-C4 alky; or

R1 is Me or Et;

R2 is an optionally substituted, optionally hetero-, optionally cyclicC1-C18 alkyl, or an optionally substituted, optionally hetero-,optionally cyclic C2-C18 alkenyl or alkynyl, or an optionallysubstituted, optionally hetero-, optionally cyclic C2-C18 aryl;

R2 is an optionally substituted C1-C4 alkyl, alkenyl or alkynyl;R2 is an optionally substituted, optionally hetero-, cyclic C5-C6 alkyl,alkenyl or alkynyl;R2 is an amine, halide or azido;

R2 is F, CH2F, CHF2, or CF3; or R2 is CF3;

R3 is an optionally substituted, heterocyclic C3-C18 hydrocarbyl;

R3 is an optionally substituted, optionally hetero-, C5-C18 or C5-C6aryl;R3 is an optionally substituted, heterocyclic, C5-C18 or C5-C6 aryl;R3 is an optionally substituted, N-heterocyclic, C3-C18 hydrocarbyl;R3 is an optionally substituted, N-heterocyclic, C5-C18 or C5-C6 aryl;R3 is an optionally substituted pyridinyl, pyrrolyl or pyrazolyl;R3 is an optionally substituted phenyl or thiophene; orR3 is an optionally substituted 5-pyridin-2(1H)-one;

R4 is H or an optionally substituted, optionally hetero-, optionallycyclic C1-C18 alkyl, or an optionally substituted, optionally hetero-,optionally cyclic C2-C18 alkenyl or alkynyl, or an optionallysubstituted, optionally hetero-, optionally cyclic C2-C18 aryl;

R4 is an optionally substituted C1-C4 alkyl, alkenyl or alkynyl;R4 is an optionally substituted, optionally hetero-, cyclic C5-C6 alkyl,alkenyl or alkynyl;R4 is H, amine, halide or azido; or

R4 is H;

R3 is an optionally substituted 5-pyridin-2(1H)-one, of formula II:

wherein:R5 is an optionally substituted, optionally hetero-, optionally cyclicC3-C18 hydrocarbyl;R5 is optionally substituted benzyl; orR5 is 3,4-dimethoxybenzyl;

and/or the compound is a disclosed compound (e.g. see Tables, herein),or is1-(3,4-dimethoxybenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H):

or a stereoisomer, hydrate, salt or acetate thereof.

In embodiments, the hydrocarbyl is an optionally substituted, optionallycyclic, C1-C10 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, or C5-C14 arylhydrocarbon, comprising 1-5 heteroatoms that are N, S, O or P, including1-5 nitrogen atoms, which heteroatoms may be substituted. Inembodiments, the hydrocarbyl is a C3-C18 cyclic hydrocarbyl, such as aheterocyclic C3-C18 hydrocarbyl, such as: a 3 membered ring that is anoptionally substituted (e.g. aziridine, oxirane, oxaziridine); a 4membered ring that is an optionally substituted (e.g. azetidine,oxetane, oxazetidine); a 5 membered ring that is an optionallysubstituted (e.g. pyrrole, 1,2-diazole (pyrazole), 1,3 diazole(imidazole), thiazole, isothiazole, oxazole, isoxazole, furan, dioxole,thiophene, triazole, furazan, tetrazole); a 6 membered ring that is anoptionally substituted (e.g. pyridine, pyran, thiopyran, diazine,triazine, oxazine, thiazine, dioxine, oxathiine, dithiine, pentazine); a7 membered ring that is optionally substituted (e.g. azapine, oxepine,thiepine, diazepine, thiazepine); a 8 membered ring that is optionallysubstituted (e.g. azocine, oxocine, thiocine); a 9 membered ring that isan optionally substituted (e.g. indole, benzothiazole, benzooxazole,benzofuran, benzodioxole, benzothiophene, benzodithiole); or a 10membered ring that is an optionally substituted (e.g. quinoline,quinoxaline, quinazoline, chromene, benzodioxine, thiochromene,benzodithiine).

In embodiments, the compound is an inhibitor or covalent modifier ofsuccinate dehydrogenase subunit B (SDHB) and/or inhibitor of apoptosis.

In embodiments, the compound is of formula I wherein R1, R2, R3 and R4are defined as follows:

Compound R₁ R₂ R₃ R₄ Hit

*—CF₃

H  1 *—CH₃ H  2 *—CH₂CH₃ H  3 *—(CH₂)₂COOEt H  4

H  5

H  6 *—Me —CH₃ H  7 —N₃ H  8

H  9

H 10 *—CF₃ phenyl H 11 2-methyl-phenyl H 12 3-methyl-phenyl H 134-methyl-phenyl H 14 2-methylbenzoate H 15 3-methylbenzoate H 164-methylbenzoate H 17 5-pyridin-2(1H)-one, Hinclusive of a corresponding sulfinyl, or a stereoisomer, hydrate, saltor acetate thereof.

In embodiments, the compound is of formula II wherein Ra is Me, R2 isCF3, R4 is H, and R5 is defined as follows: compound R5

compound R₅ 17 —H 18 -benzyl 19 2-chlorobenzyl 20 3-chlorobenzyl 214-chlorobenzyl 22 3-hydroxybenzyl 23 3-methoxybenzyl 24 3-ethoxybenzyl25 3-propoxybenzyl 26 4-methoxybenzyl 27 3,4-dimethoxybenzyl 282-propynyl 29 4-methoxy-3-(2-propynyl loxy)benzyl 30

31

32 3-methoxy-4-(2-propynyl loxy)benzyl 33 3-ethynylbenzene 344-ethynylbenzene 35

again, inclusive of a corresponding sulfinyl, or a stereoisomer,hydrate, salt or acetate thereof.

In embodiments the invention provides a pharmaceutical compositioncomprising a disclosed compound or composition in unit dosage form,and/or coformulated or copackaged or coadministered with a differentanti-Parkinson's drug

The invention also provides methods of using a disclosed compound orcomposition comprising administering it to a person determined to be inneed thereof, and optionally, detecting a resultant therapeutic effect,and may also optionally include the antecedent step of determining thatthe person, particularly diagnosing and applicable disease or condition(herein), or use thereof in the manufacture of a medicament.

The invention encompasses all combination of the particular embodimentsrecited herein, as if each combination had been laboriously recited.

DESCRIPTION OF PARTICULAR EMBODIMENTS OF THE INVENTION

The following descriptions of particular embodiments and examples areprovided by way of illustration and not by way of limitation. Thoseskilled in the art will readily recognize a variety of noncriticalparameters that could be changed or modified to yield essentiallysimilar results.

Unless contraindicated or noted otherwise, in these descriptions andthroughout this specification, the terms “a” and “an” mean one or more,the term “or” means and/or and polynucleotide sequences are understoodto encompass opposite strands as well as alternative backbones describedherein. Furthermore, genuses are recited as shorthand for a recitationof all members of the genus; for example, the recitation of (C1-C3)alkyl is shorthand for a recitation of all C1-C3 alkyls: methyl, ethyland propyl, including isomers thereof.

A hydrocarbyl group is a substituted or unsubstituted, straight-chain,branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl,arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl groupwhich comprises 1-15 carbon atoms and optionally includes one or moreheteroatoms in its carbon skeleton.

The term “heteroatom” as used herein generally means any atom other thancarbon or hydrogen. Preferred heteroatoms include oxygen (O), phosphorus(P), sulfur (S), nitrogen (N), and halogens, and preferred heteroatomfunctional groups are haloformyl, hydroxyl, aldehyde, amine, azo,carboxyl, cyanyl, thocyanyl, C(O)R (e.g. carbonyl), halo, hydroperoxyl,imine, aldimine, isocyanide, iscyante, nitrate, nitrile, nitrite, nitro,nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, and sulfhydryl.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which is fully saturated,having the number of carbon atoms designated (i.e. C1-C8 means one toeight carbons). Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,(cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.

The term “alkenyl”, by itself or as part of another substituent, means astraight or branched chain, or cyclic hydrocarbon radical, orcombination thereof, which may be mono- or polyunsaturated, having thenumber of carbon atoms designated (i.e. C2-C8 means two to eightcarbons) and one or more double bonds. Examples of alkenyl groupsinclude vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl) and higher homologs and isomersthereof.

The term “alkynyl”, by itself or as part of another substituent, means astraight or branched chain hydrocarbon radical, or combination thereof,which may be mono- or polyunsaturated, having the number of carbon atomsdesignated (i.e. C2-C8 means two to eight carbons) and one or moretriple bonds. Examples of alkynyl groups include ethynyl, 1- and3-propynyl, 3-butynyl and higher homologs and isomers thereof.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from alkyl, as exemplified by—CH₂—CH₂—CH₂—CH₂—. Typically, an alkyl (or alkylene) group will havefrom 1 to 24 carbon atoms, with those groups having 10 or fewer carbonatoms being preferred in the invention. A “lower alkyl” or “loweralkylene” is a shorter chain alkyl or alkylene group, generally havingeight or fewer carbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and from one to three heteroatoms selectedfrom the group consisting of O, N, P, Si and S, wherein the nitrogen,sulfur, and phosphorous atoms may optionally be oxidized and thenitrogen heteroatom may optionally be quaternized. The heteroatom(s) O,N, P and S may be placed at any interior position of the heteroalkylgroup. The heteroatom Si may be placed at any position of theheteroalkyl group, including the position at which the alkyl group isattached to the remainder of the molecule. Examples include—CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃,—CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃,—CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may beconsecutive, such as, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃.

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent means a divalent radical derived from heteroalkyl, asexemplified by —CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. Forheteroalkylene groups, heteroatoms can also occupy either or both of thechain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino,alkylenediamino, and the like). Still further, for alkylene andheteroalkylene linking groups, no orientation of the linking group isimplied.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Accordingly, acycloalkyl group has the number of carbon atoms designated (i.e., C3-C8means three to eight carbons) and may also have one or two double bonds.A heterocycloalkyl group consists of the number of carbon atomsdesignated and from one to three heteroatoms selected from the groupconsisting of O, N, Si and S, and wherein the nitrogen and sulfur atomsmay optionally be oxidized and the nitrogen heteroatom may optionally bequaternized. Additionally, for heterocycloalkyl, a heteroatom can occupythe position at which the heterocycle is attached to the remainder ofthe molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include 1-(1,2,5,6-tetrahydropyrid-yl), 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl,tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” and “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include alkyl substituted with halogen atoms, which can be thesame or different, in a number ranging from one to (2m′+1), where m′ isthe total number of carbon atoms in the alkyl group. For example, theterm “halo(C1-C4)alkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Thus,the term “haloalkyl” includes monohaloalkyl (alkyl substituted with onehalogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms ina number ranging from two to (2m′+1) halogen atoms, where m′ is thetotal number of carbon atoms in the alkyl group). The term“perhaloalkyl” means, unless otherwise stated, alkyl substituted with(2m′+1) halogen atoms, where m′ is the total number of carbon atoms inthe alkyl group. For example the term “perhalo(C1-C4)alkyl” is meant toinclude trifluoromethyl, pentachloroethyl,1,1,1-trifluoro-2-bromo-2-chloroethyl and the like.

The term “acyl” refers to those groups derived from an organic acid byremoval of the hydroxy portion of the acid. Accordingly, acyl is meantto include, for example, acetyl, propionyl, butyryl, decanoyl, pivaloyl,benzoyl and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon substituent which can be a single ringor multiple rings (up to three rings) which are fused together or linkedcovalently. Non-limiting examples of aryl groups include phenyl,1-naphthyl, 2-naphthyl, 4-biphenyl and 1,2,3,4-tetrahydronaphthalene.

The term heteroaryl,” refers to aryl groups (or rings) that containfrom/zero to four heteroatoms selected from N, O, and S, wherein thenitrogen and sulfur atoms are optionally oxidized and the nitrogenheteroatom are optionally quaternized. A heteroaryl group can beattached to the remainder of the molecule through a heteroatom.Non-limiting examples of heteroaryl groups include 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl,pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl,purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like) including thosealkyl groups in which a carbon atom (e.g., a methylene group) has beenreplaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) is meant to include both substituted and unsubstitutedforms of the indicated radical. Preferred substituents for each type ofradical are provided below.

Substituents for the alkyl and heteroalkyl radicals (as well as thosegroups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl,alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl andheterocycloalkenyl) can be a variety of groups selected from: —OR′, ═O,═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO₂NR′,—NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′,—SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN and —NO₂, in a number ranging from/zeroto three, with those groups having zero, one or two substituents beingparticularly preferred. R′, R″ and R′″ each independently refer tohydrogen, unsubstituted (C1-C8)alkyl and heteroalkyl, unsubstitutedaryl, aryl substituted with one to three halogens, unsubstituted alkyl,alkoxy or thioalkoxy groups, or aryl-(C1-C4)alkyl groups. When R′ and R″are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 5-, 6- or 7-membered ring. For example, —NR′R″is meant to include 1-pyrrolidinyl and 4-morpholinyl. Typically, analkyl or heteroalkyl group will have from/zero to three substituents,with those groups having two or fewer substituents being preferred inthe invention. More preferably, an alkyl or heteroalkyl radical will beunsubstituted or monosubstituted. Most preferably, an alkyl orheteroalkyl radical will be unsubstituted. From the above discussion ofsubstituents, one of skill in the art will understand that the term“alkyl” is meant to include groups such as trihaloalkyl (e.g., —CF₃ and—CH₂CF₃).

Preferred substituents for the alkyl and heteroalkyl radicals areselected from: —OR′, ═O, —NR′R″, —SR′, halogen, —SiR′R″R′″, —OC(O)R′,—C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′,—NR′—SO₂NR″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN and —NO₂,where R′ and R″ are as defined above. Further preferred substituents areselected from: —OR′, ═O, —NR′R″, halogen, —OC(O)R′, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′, —NR′—SO₂NR″R′″, —SO₂R′, —SO₂NR′R″,—NR″SO₂R, —CN and —NO₂.

Similarly, substituents for the aryl and heteroaryl groups are variedand selected from: halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN,—NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″CO2R′,—NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″, —NH—C(NH2)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —N₃, —CH(Ph)₂,perfluoro(C1-C4)alko-xy and perfluoro(C1-C4)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R′, R″ and R′″ are independently selected fromhydrogen, (C1-C8)alkyl and heteroalkyl, unsubstituted aryl andheteroaryl, (unsubstituted aryl)-(C1-C4)alkyl and (unsubstitutedaryl)oxy-(C1-C4)alkyl. When the aryl group is1,2,3,4-tetrahydronaphthalene, it may be substituted with a substitutedor unsubstituted (C3-C7)spirocycloalkyl group. The(C3-C7)spirocycloalkyl group may be substituted in the same manner asdefined herein for “cycloalkyl”. Typically, an aryl or heteroaryl groupwill have from/zero to three substituents, with those groups having twoor fewer substituents being preferred in the invention. In oneembodiment of the invention, an aryl or heteroaryl group will beunsubstituted or monosubstituted. In another embodiment, an aryl orheteroaryl group will be unsubstituted.

Preferred substituents for aryl and heteroaryl groups are selected from:halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′, —CONR′R″,—C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R,—N₃, —CH(Ph)₂, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, whereR′ and R″ are as defined above. Further preferred substituents areselected from: halogen, —OR′, —OC(O)R′, —NR′R″, —R′, —CN, —NO₂, —CO₂R′,—CONR′R″, —NR″C(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R,perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl.

The substituent —CO₂H, as used herein, includes bioisostericreplacements therefor; see, e.g., The Practice of Medicinal Chemistry;Wermuth, C. G., Ed.; Academic Press: New York, 1996; p. 203.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)q-U—, wherein T and U are independently —NH—, —O—, —CH₂— ora single bond, and q is an integer of from 0 to 2. Alternatively, two ofthe substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula -A-(CH2)r-B—,wherein A and B are independently —CH₂—, —O—, —NH—, —S—, —S(O)—,—S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integer of from 1 to3. One of the single bonds of the new ring so formed may optionally bereplaced with a double bond. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula —(CH₂)s-X—(CH₂)t-, where s and t areindependently integers of from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—,—S(O)₂—, or —S(O)₂NR′—. The substituent R′ in —NR′— and —S(O)₂NR′— isselected from hydrogen or unsubstituted (C1-C6)alkyl.

Preferred substituents are disclosed herein and exemplified in thetables, structures, examples, and claims, and may be applied acrossdifferent compounds of the invention, i.e. substituents of any givencompound may be combinatorially used with other compounds.

In particular embodiments applicable substituents are independentlysubstituted or unsubstituted heteroatom, substituted or unsubstituted,optionally heteroatom C1-C6 alkyl, substituted or unsubstituted,optionally heteroatom C2-C6 alkenyl, substituted or unsubstituted,optionally heteroatom C2-C6 alkynyl, or substituted or unsubstituted,optionally heteroatom C6-C14 aryl, wherein each heteroatom isindependently oxygen, phosphorus, sulfur or nitrogen.

In more particular embodiments, applicable substituents areindependently aldehyde, aldimine, alkanoyloxy, alkoxy, alkoxycarbonyl,alkyloxy, alkyl, amine, azo, halogens, carbamoyl, C(O)R (e.g. carbonyl),carboxamido, carboxyl, cyanyl, ester, halo, haloformyl, hydroperoxyl,hydroxyl, imine, isocyanide, iscyante, N-tert-butoxycarbonyl, nitrate,nitrile, nitrite, nitro, nitroso, phosphate, phosphono, sulfide,sulfonyl, sulfo, sulfhydryl, thiol, thiocyanyl, trifluoromethyl ortrifluromethyl ether (OCF3).

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the invention containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts includesodium, potassium, calcium, ammonium, organic amino, or magnesium salt,or a similar salt. When compounds of the invention contain relativelybasic functionalities, acid addition salts can be obtained by contactingthe neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginate and the like, and salts of organic acids likeglucuronic or galactunoric acids and the like. Certain specificcompounds of the invention contain both basic and acidic functionalitiesthat allow the compounds to be converted into either base or acidaddition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the invention.

In addition to salt forms, the invention provides compounds which are ina prodrug form. Prodrugs of the compounds described herein are thosecompounds that undergo chemical changes under physiological conditionsto provide the compounds of the invention. Additionally, prodrugs can beconverted to the compounds of the invention by chemical or biochemicalmethods in an ex vivo environment. For example, prodrugs can be slowlyconverted to the compounds of the invention when placed in a transdermalpatch reservoir with a suitable enzyme or chemical reagent. Prodrugs areoften useful because, in some situations, they may be easier toadminister than the parent drug. They may, for instance, be morebioavailable by oral administration than the parent drug. The prodrugmay also have improved solubility in pharmacological compositions overthe parent drug. A wide variety of prodrug derivatives are known in theart, such as those that rely on hydrolytic cleavage or oxidativeactivation of the prodrug. An example, without limitation, of a prodrugwould be a compound of the invention which is administered as an ester(the “prodrug”), but then is metabolically hydrolyzed to the carboxylicacid, the active entity. Additional examples include peptidylderivatives of a compound of the invention.

Certain compounds of the invention can exist in unsolvated forms as wellas solvated forms, including hydrated forms. In general, the solvatedforms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the invention. Certain compounds of theinvention may exist in multiple crystalline or amorphous forms. Ingeneral, all physical forms are equivalent for the uses contemplated bythe invention and are intended to be within the scope of the invention.

Some of the subject compounds possess asymmetric carbon atoms (opticalcenters) or double bonds; the racemates, diastereomers, geometricisomers and specifically designated or depicted chirality is preferredand in many cases critical for optimal activity; however all suchisomers are all intended to be encompassed within the scope of theinvention.

The compounds of the invention may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe invention, whether radioactive or not, are intended to beencompassed within the scope of the invention.

The term “therapeutically effective amount” refers to the amount of thesubject compound that will elicit, to some significant extent, thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician, such as when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof the condition or disorder being treated. The therapeuticallyeffective amount will vary depending on the compound, the disease andits severity and the age, weight, etc., of the mammal to be treated.

The invention also provides pharmaceutical compositions comprising thesubject compounds and a pharmaceutically acceptable excipient,particularly such compositions comprising a unit dosage of the subjectcompounds, particularly such compositions copackaged with instructionsdescribing use of the composition to treat an applicable disease orcondition (herein).

The compositions for administration can take the form of bulk liquidsolutions or suspensions, or bulk powders. More commonly, however, thecompositions are presented in unit dosage forms to facilitate accuratedosing. The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient. Typical unit dosage forms includeprefilled, premeasured ampules or syringes of the liquid compositions orpills, tablets, capsules, losenges or the like in the case of solidcompositions. In such compositions, the compound is usually a minorcomponent (from about 0.1 to about 50% by weight or preferably fromabout 1 to about 40% by weight) with the remainder being variousvehicles or carriers and processing aids helpful for forming the desireddosing form.

Suitable excipients or carriers and methods for preparing administrablecompositions are known or apparent to those skilled in the art and aredescribed in more detail in such publications as Remington'sPharmaceutical Science, Mack Publishing Co, NJ (1991). In addition, thecompounds may be advantageously used in conjunction with othertherapeutic agents as described herein or otherwise known in the art,particularly other anti-diabetes or anti-obesity agents. Hence thecompositions may be administered separately, jointly, or combined in asingle dosage unit.

The amount administered depends on the compound formulation, route ofadministration, etc. and is generally empirically determined in routinetrials, and variations will necessarily occur depending on the target,the host, and the route of administration, etc. Generally, the quantityof active compound in a unit dose of preparation may be varied oradjusted from about 1, 3, 10 or 30 to about 30, 100, 300 or 1000 mg,according to the particular application. In a particular embodiment,unit dosage forms are packaged in a multipack adapted for sequentialuse, such as blisterpack, comprising sheets of at least 6, 9 or 12 unitdosage forms. The actual dosage employed may be varied depending uponthe requirements of the patient and the severity of the condition beingtreated. Determination of the proper dosage for a particular situationis within the skill of the art. Generally, treatment is initiated withsmaller dosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small amounts until the optimumeffect under the circumstances is reached. For convenience, the totaldaily dosage may be divided and administered in portions during the dayif desired.

The compounds can be administered by a variety of methods including, butnot limited to, parenteral, topical, oral, or local administration, suchas by aerosol or transdermally, for prophylactic and/or therapeutictreatment. Also, in accordance with the knowledge of the skilledclinician, the therapeutic protocols (e.g., dosage amounts and times ofadministration) can be varied in view of the observed effects of theadministered therapeutic agents on the patient, and in view of theobserved responses of the disease to the administered therapeuticagents.

The therapeutics of the invention can be administered in atherapeutically effective dosage and amount, in the process of atherapeutically effective protocol for treatment of the patient. Formore potent compounds, microgram (ug) amounts per kilogram of patientmay be sufficient, for example, in the range of about 1, 10 or 100 ug/kgto about 0.01, 0.1, 1, 10, or 100 mg/kg of patient weight though optimaldosages are compound specific, and generally empirically determined foreach compound.

In general, routine experimentation in clinical trials will determinespecific ranges for optimal therapeutic effect, for each therapeutic,each administrative protocol, and administration to specific patientswill also be adjusted to within effective and safe ranges depending onthe patient condition and responsiveness to initial administrations.However, the ultimate administration protocol will be regulatedaccording to the judgment of the attending clinician considering suchfactors as age, condition and size of the patient as well as compoundspotency, severity of the disease being treated. For example, a dosageregimen of the compounds can be oral administration of from 10 mg to2000 mg/day, preferably 10 to 1000 mg/day, more preferably 50 to 600mg/day, in two to four (preferably two) divided doses. Intermittenttherapy (e.g., one week out of three weeks or three out of four weeks)may also be used.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein, including citations therein, are herebyincorporated by reference in their entirety for all purposes.

EXAMPLES

Highly Potent Apoptosis Inhibitors that Target the MitochondrialRespiratory Chain

Here, we report the development of a series of unique and highly potentapoptosis inhibitors (TC09 series). They have low-nanomolar EC₅₀ values,and target events in the apoptosis signaling pathway that occur betweenthe regulation of Bcl-2 family proteins and mitochondrial cytochrome crelease. Target identification based on affinity based protein profiling(ABPP) revealed that the molecular target of TC09 apoptosis inhibitorcompounds is succinate dehydrogenase subunit B (SDHB) of mitochondrialrespiratory complex II.

A chemical library containing 200,000 small molecules was screened forcompounds that block apoptosis using a cell line with inducibleoverexpression of Bim (U2OS_Bim). [7] Several active hits wereidentified, and these had an EC50 between 2 to 20 μM in increasing cellsurvival rates following apoptosis as induced by Bim overexpression.Mitochondrial release of cytochrome c was checked by immunofluorescenceassays to detect if these hits functioned upstream ofapoptosis-associated mitochondrial changes that occur after the inducedBimprotein overxepression One hit with an EC₅₀ of 4.0 μM could preventcytochrome c release: this compound was selected for furtheroptimization (TC09-hit, Table 1).

We undertook a structure activity relationship based optimization withthe aim of improving the activity of the screening hit. We initiallyoptimized fragment R₁ (Table 1). In each case, replacement of R₁ withaliphatic groups of varying sizes increased the apoptosis inhibitionactivity by 3-5 fold (compound 1-3). Aromatic substitutes were alsotested, and activity remained at similar levels as the hit. (compound4,5) This indicated that fragment R₁ could tolerate a relatively largechange in structure. Since compound 1 had the strongest apoptosisinhibition activity, we replaced the original structure of R₁ with amethyl group for further SAR study. We next substituted the —CF₃ groupat the R₂ position with different groups-, all such variations led tothe total loss of activity. (compounds 6-9) This may relate to either aconstrained binding environment or the necessity of the strong electronwithdrawing property of the original —CF₃ group.

TABLE 1 SAR study of compounds TC09 1-17

EC₅₀ Compound R₁ R₂ R₃ (nM) Hit

*—CF₃

4010  1 *—CH₃ 749  2 *—CH₂CH₃ 1428  3 *—(CH₂)₂COOEt 1135  4

4207  5

1172  6 —CH₃ >20000  7 —N₃ >20000  8

>20000  9

>20000 10 *—Me *—CF₃ phenyl 2201 11 2-methyl-phenyl 6642 123-methyl-phenyl 3487 13 4-methyl-phenyl 6355 14 2-methylbenzoate 7033 153-methylbenzoate 3516 16 4-methylbenzoate >20000 17 5-pyridin-2(1H)-one>20000

We then conducted SAR optimization of fragment R₃ (Table 1). Althoughthe replacement of the original thiophene group with phenyl rings (10)resulted in decreased activity, it did offer more options for testingthe influence of substitutes on different positions of the ring.Compounds with methyl substitution at the 2-, 3-, and 4-positions of thephenyl ring showed different trends in their activity (compounds 11-13).Methyl substitution at both the 2- and 4-positions (11, 13) led to a 3fold decreases in activity compared with compound 10, while methylsubstitution at the 3-position (compound 12) had a similar EC₅₀ tocompound 10. Additionally, activity of compounds with —COOCH₃substitution at 2, 3, 4-position shared similar pattern that only3-substitution kept the activity (compounds 14-16). These results hintedthat the area near 3-position of phenyl ring had a bigger tolerance thanother positions. We then synthesized compound 17, by replacing theoriginal thiophene group with a pyridone ring. It served as anintermediate for further SAR exploration at 3-position, and the activitywas completely lost. However, the addition of a benzyl group to the Natom in the pyridone (compound 18) restored the activity to an EC₅₀ of1157 nM. (Table 2) This interesting finding indicates that extending theskeleton of the compound by adding the benzyl ring may form newinteraction(s) with the target.

TABLE 2 SAR study of compounds TC09 13-35

EC₅₀ compound R₄ (nM) 17 —H >20000 18 -benzyl 1157 19 2-chlorobenzyl1143 20 3-chlorobenzyl 257 21 4-chlorobenzyl 66 22 3-hydroxybenzyl 141523 3-methoxybenzyl 57 24 3-ethoxybenzyl 110 25 3-propoxybenzyl 69 264-methoxybenzyl 94 27 3,4-dimethoxybenzyl 13 28 2-propynyl 499 294-methoxy-3-(2-propynyl loxy)benzyl 104 30

4877 31

>20000 32 3-methoxy-4-(2-propynyl loxy)benzyl 64 33 3-ethynylbenzene4477 34 4-ethynylbenzene 817 35

995

Encouraged by these results, exploration of SAR on the benzyl ring wasthen performed in more details. Chloro-substitution at differentpositions of the benzyl ring (compounds 19-21) was examined. As shown inTable 2, the 2-chloro compound 19 had only a mild increase in activitycompared with compound 18, but 3- and 4-chloro compounds 20 and 21 wereboth found to be more potent in inhibiting apoptosis. Compound 20 had anEC₅₀ of 257 nM, about 4 fold more potent than compound 18. Compound 21was 17 fold more potent than compound 18. We next focused onsubstitution on the 3- and 4-positions of the benzyl ring. 3-position—OH, —OMe, —OEt, and —OPr substituted compounds were all synthesized andtested (compounds 22-25). The compound with 3-OH substitution had thesame activity as compound 18, and was less potent than the 3-chlorocompound 20. Addition of a methyl group at the oxygen atom (compound 23)raised the activity by about 20 fold; its EC₅₀ was only 57 nM. —OEt and—OPr substituted compounds 24 and 25 also displayed similar enhancementsas compound 23 in activity. The influence of 4-OMe substitution(compound 26) was then examined, and the same as 3-OMe substitution, italso promoted the activity by ˜12 folds compared with compound 18.Enlightened by compounds 23 and 26, we next combined 3- and 4-position—OMe substitutions in compound 27(1-(3,4-dimethoxybenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H),which showed a yet further increased inhibition activity, with an EC₅₀as low as 11 nM, more than 300 fold higher than with the initial hitcompound.

In addition to testing the apoptosis inhibition activity of TC09compounds on Bim-induced apoptosis, we also evaluated if they couldblock apoptosis as induced by the overexpression of tBid, anotherpro-apoptotic protein of the Bcl-2 family. Comparable inhibition potencyproperties were observed in both apoptosis induction models, and thebest compound 27 reached an EC₅₀ of 66 nM. To the best of our knowledge,TC09 compounds are the first to fully inhibit apoptosis at thelow-nanomolar level in a cellular assay.

It has been reported that sulfone can serve as a good leaving group inSN₂ substitution reactions when linked to electron withdrawing groups.[8] Active compounds in our SAR study all contained a —CF₃ substitutedpyrimidine ring linked to the sulfone group. Replacement of CF₃ at theR₂ position with groups with less powerful electron-withdrawingproperties totally abolished the apoptosis inhibition activity. The factthat the observed variation in apoptosis inhibition activity correlatedwith changes in the electrophilicity of the fragment linked to thesulfone group suggested that TC09 compounds may function via covalentbinding through an SN₂ substitution reaction with nucleophilic residues.To test the reactivity of representative TC09 compounds, we performedmodel reactions using different nucleophilic reagent (cysteine, lysine,and glutathione) with compounds 1, 6, and 27. LC-MS analysis of reactionindicated that nucleophilic substitution products of compound 1 and 27were observed in the reactions with cysteine and glutathione, but not inthe lysine reactions. No products of compound 6 were observed in any ofthe nucleophilic reagent reactions. To further explore the binding modeof the active compounds in a cellular context, we next performed acellular wash/no wash assay for determining the reversibility ofcompound-target interactions. Following compound incubation, one subsetof cells was washed several times to eliminate the free test compounds,and the other subset was not washed. Apoptosis was induced and theviability of cells was then measured and EC₅₀ under wash conditions wascompared with no wash conditions.[9] Most of the compounds had a similarEC₅₀ values under these two conditions (Table 3), indicating anirreversible binding mode between these compounds and the target.Results from both the model reactions and the cellular assays indicatedthat TC09 apoptosis inhibitors function through covalent binding withthe target, and possibly through —SH residue attack.

TABLE 3 Comparision of EC₅₀ values between the wash and no wash assayEC₅₀ (no EC₅₀ (wash EC₅₀ (no EC₅₀ (wash compound wash, nM) assay, nM)compound wash, nM) assay, nM) 1 749 661 25 69 66 3 1135 1268 26 94 16810 2201 5058 27 13 7 17 1157 1069 28 499 499 19 1143 997 29 104 55 20257 305 hit 4010 3895 21 66 45 zVAD 69217 n.d. 23 57 62

Given that TC09 apoptosis inhibitors function upstream of mitochondrialcytochrome c release to inhibit apoptosis and maintain cell survival, wenext examined if they could block the dysfunction of mitochondria thatoccurs following the induction of apoptosis. We first measured changesin the mitochondrial membrane potential using TMRM, a fluorescent dyeunder different conditions. Dox induction of Bim overexpression is knownto result in the loss of mitochondrial membrane potential and thusdiminish TMRM enrichment during apoptosis. Compounds at concentrationthat are completely block apoptosis can maintain the mitochondriamembrane potential and TMRM enrichment, an outcome that cannot beachieved with zVAD, a caspase inhibitor. The mitochondria protectioneffect of TC09 compounds was also supported by the measurement of ROSlevels after apoptosis induction. ROS level is upregulated due to theinterruption of the electron transport chain and the changes of membranepermeability that occur during apoptosis, and the over-produced ROSagain act as a stimulative factor and cause further damage[13]. TC09compounds treatment maintained the normal ROS level even upon apoptosisinduction, and showed a dose-dependent effect.

In order to identify the target protein of tTC09 apoptosis inhibitors,we synthesized two sets of probes for target identification based on theSAR study. The first set of probes was designed for direct activitybased protein profiling (ABPP) with biotin tag linked at different site.The addition of these biotin tags resulted in varying degrees ofactivity loss, possibly owing to steric hindrance of the bulky fragmentor a change of cellular permeability (Table 2). Compounds 30 and 31 wereselected as positive and negative probes for pulldown assays andidentified succinate dehydrogenase subunit B (SDHB), a component of therespiratory complex II located on the mitochondrial inner membrane, asthe covalent binding target. TC09 apoptosis inhibitors could stabilizethe mitochondrial respiratory chain after Bim/tBid overexpression andhelp maintain the normal function of mitochondria. A second set ofprobes with a terminal alkyne group designed for click-reaction-assistedABPP were also prepared. Most of these compounds (28, 29, 32-34)retained relatively potent activity, with EC₅₀ values below 1 μM.Click-reaction-assisted ABPP was performed using compound 29 as apositive probe and compound 27 as a competitor; these probes alsoidentified SDHB as the cellular target. To further verify that SDHB wasindeed the molecular target, we also synthesized a derivative ofcompound 29 with an FITC tag for fluorescence imaging (compound 35,EC₅₀=995 nM). The green fluorescence of compound 35 merged well with thespecific red fluorescent staining of mitochondria, indicating that mostof compound 35 was localized in mitochondria.

TC09 Compounds Save Cells from Apoptotic Insults

Despite intensive efforts, researchers have as yet failed to identify asmall molecule that can confer long-term survivability to cells when themitochondrial apoptosis pathway is activated. The pan-caspase inhibitorz-VAD-FMK is able to keep cells alive (as measured by cellular ATPlevels) during a short time frame (usually less than 24 hours), but isnot able to save cells from death when the upstream insults tomitochondria persist.

We therefore tested the long-term impact of TC09 compounds on cellsexperiencing constant apoptotic insult. Control U2OS_Bim cellscompletely died off within 24 hours after the addition of DOX, andalthough the presence of z-VAD-FMK clearly delayed death, most of thecells had died by the third day. Remarkably, in the presence of testedTC09 compounds, the cells continued to proliferate, similar to cellsgrown under normal conditions.

The long-term cell survivability conferred by TC09 compounds was againdemonstrated when the cells were cultured for 1 week and the resultingcell colonies were visualized with crystal violet dye. The U2OS_Bimcells were all killed when DOX was added, even in the presence ofz-VAD-FMK. In contrast, when a TC09 compound was present, the cellcolonies grown in the media containing DOX were indistinguishable fromthe ones grown without DOX, demonstrating that TC09 compounds, unlikethe caspase inhibitors that only delay cell death, are able to keep thecells alive and proliferating even after their mitochondrial apoptoticpathway has been activated.

TC09 Compounds are Effective in Protecting Neuronal Death in an AnimalModel of Parkinson's Disease

The remarkable cell-protection effect of TC09 compounds that we observedwith our in vitro experiments prompted us to test if the compounds showsimilar effects in in vivo experiments. For this purpose, we chose a6-OHDA-induced Parkinson's disease model in rat. The injection of thedopamine derivative 6-OHDA into the medial forebrain bundle region ofthe rat brain caused specific depletion of dopaminergic neurons in thesubstantial nigra region. The co-injection of increasing amounts of anexemplary TC09 compound (compound 27) showed dose-dependent protectionof these neurons, while an inactive derivative, even at the highestinjected concentration, did not show any protective effect. Treatmentwith the TC09 compound alone did not increase the area of thesubstantial nigra region, indicating that the effect of the TC09compound occurred via cell protection, not from increased cellproliferation. The protective effect of the TC09 compound did not resultfrom a chemical reaction that neutralized 6-OHDA, as similar amounts of6-OHDA were detected in rat brain tissue regardless of the presence orabsence of Compound A. The dopaminergic neurons protected by the TC09compound appeared to be functional, as the Parkinson-like behavior of6-OHDA-injected rats was corrected by the TC09 compound. We concludedthat TC09 compounds can confer dose-dependent protection of thedopaminergic neurons and correct the neurological phenotype associatedwith the disease

It is known that excessive apoptosis plays an important role inneurological disorders, and we established that TC09 compounds canconfer a protective effect in a mouse model of Parkinson's disease.Here, we tested the potential therapeutic bioactivity of TC09 compoundsin an ischemia model in rat. Following cerebral ischemia, it is knownthat BH3-only proteins are upregulated and activate the intrinsicapoptosis pathway and that caspase inhibitors can attenuate the volumeof dead tissue in focal ischemia. For in vivo evaluation, a transientfocal cerebral ischemia was induced by middle cerebral artery occlusion(MCAO) in rats. Injection of TC09 compound showed a dose-dependentprotection effect; treatment reduced brain infarct volume afterinduction of focal cerebral ischemia, thereby demonstrating theapplication of TC09 compounds for neuron protection.

In conclusion, we have developed a unique series of irreversibleapoptosis inhibitors based on an initial hit from high-throughputscreening and SAR optimization, and improved the cellular activity to anEC₅₀ at the low-nanomolar level. These compounds bond covalently withthe SDHB subunit of mitochondrial respiratory complex II and confermitochondrial protection effects by stabilizing mitochondrialrespiratory chain, maintaining the mitochondrial membrane potential, andinhibiting ROS generation. The compounds also show remarkable protectioneffect in transient focal cerebral ischemia, further demonstrating theirapplication as novel therapies for excessive apoptosis related diseases.

Experimental Protocol

High-Throughput Screening

A chemical library containing 200000 compounds was screened according tothe following procedure: U2OS_Bim cells (a cell line in which theBH3-only protein Bim can be inducibly expressed by the addition ofDoxycycline to the growth medium)^([2]) were plated in 384-well plateswith 30 μl medium at a density of 500 cells per well. 16 hrs afterplating, test compounds were transferred from stock plates to the assayplates with the cultured cells. Positive control (20 μM zVAD) andnegative control (DMSO) were added to every plate. 1 hr after compoundtreatment, 0.1 ug/mL Doxycyclin (DOX) was added to induce the expressionof the Bim protein. After 24 hrs, cell viability was determined bymeasuring the ATP levels using a Cell Titer-Glo kit (Promega, G7570)according to the manufacturer's instructions. Luminescence was recordedwith a PerkinElmer EnSpire Multimode Plate Reader. Compounds that couldrescue cell viability to a level above 50% were selected; thesecompounds were then screened a second time for assurance.

Immunostaining of Cytochrome c

U2OS_Bim cells were plated in Lab-Tek eight-chambered slides (ThermoScientific). 24 hrs later, cells were treated with experimentalcompounds for one hour. Cell were washed by PBS for 10 min and fixedwith 2% PFA for 30 min at room temperature. Following three additionalwashes in PBS, cells were incubated in PBS containing 0.1% Triton X-100for 10 min. Cytochrome c antibody (diluted in 5% BSA in PBST) wasincubated with the cells at 4° C. overnight. Cells were then washedthree times with PBST and incubated with secondary antibody at roomtemperature for 1 h. Following three additional washes in PBS, theslides were covered and sealed and then examined with a Zeiss LSM 510confocal microscope.

Apoptosis Inhibition Assay

U2OS_Bim or U2OS_tBid cells were plated at a density of 3000 cells perwell in 96-well plates. 24 hrs later, cells were treated withexperimental compounds, zVAD (positive control) and DMSO (Negativecontrol) for one hour. The cells were then treated with 0.1 μg/mL DOX totrigger apoptosis. 24 hours after the addition of DOX, cell viabilitywas determined by measuring the ATP levels using a Cell Titer-Glo kit.Cell survival rate was calculated.

Irreversibility Binding Assay

U2OS_Bim cells were plated at a density of 3000 cells per well in96-well plates. 24 hrs later, duplicate sets of cells were treated withexperimental compounds for 3 hrs. One subset of these cells were treatedwith 0.1 μg/mL DOX to trigger apoptosis. The remaining subset of cellswas washed free of the experimental compound using warmed medium, 3times, before being treated with 0.1 μg/mL DOX. 24 hours after DOXaddition, cell viability was determined by measuring the ATP levelsusing a CellTiter-Glo kit. Cell survival rate was calculated. zVAD (20μM) was used as a positive control.

TMRM Staining

U2OS_Bim cells were plated at a density of 3000 cells per well in96-well optical plates. 24 hrs later, cells were treated withexperimental compounds for one hour. The cells were then treated with0.1 μg/mL DOX to trigger apoptosis. 4 hrs later, 50 nM TMRM was added toeach well and incubated for 30 min. Cells were washed 3 times withwarmed PBS buffer and examined with a Zeiss LSM 510 confocal microscope.

ROS Measurement

U2OS_Bim cells were plated at a density of 3000 cells per well in96-well optical plate. 24 hrs later, cells were treated withexperimental compounds for 2 hrs. The cells were then treated with 0.1μg/mL DOX to trigger apoptosis. 4 hrs later, cells were washed 3 timeswith PBS and then incubated in PBS with 2 μM DCFH-DA for 30 min at 37°C. Cells were then washed twice with PBS and fluorescence was detectedwith a PerkinElmer EnSpire Multimode Plate Reader (λ_(ex)=485 nm andλ_(em)=525 nm). As a positive control, following the DCFH-DA incubationand PBS washing, 50 μM of H₂O₂ was added to untreated cells and followedby fluorescence analysis. Immediately after fluorescence detection, cellviability was determined by measuring the ATP levels using aCellTiter-Glo kit. Mean ROS levels were recorded as ROSfluorescence/cell viability, and the ratio of ROS increase wascalculated. Data are represented as means±standard deviation ofduplicates.

Click-Assisted, Activity-Based Protein Profiling

U2OS_Bim cells were treated with competitor compound 27 for 1 hr inarrange of concentration from 20 μM to 200 μM. Compound 27 was thenwashed off with PBS (3 washes), and of 20 μM compound 29 was added andincubated for 3 hrs. Cells were then lysed and the lysate was adjustedto a concentration of 1 mg/mL protein. Click reactions were performedwith compound biotin-N₃(N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide)(500 μM), TBTA (500 μM), CuSO₄ (1 mM), and sodium L-ascorbate (1 mM) for1 hr at 37° C. Lysates were then precipitated using 5 volumes ofmethanol, washed 3 times with methanol, and then redissolved with 1 mLPBS buffer containing 0.2% SDS. 200 uL of streptavidin agrose was addedto each sample. Samples were incubated for 2 hr at room temperature,centrifuged at 3000 rpm for 3 min, and then washed 3 times with PBSbuffer. 30 ul 1× loading buffer was used for elution. Sample elutateswere then used in Western blot detecting biotin and SDHB.

Cellular Fluorescence Staining

U2OS_Bim cells were plated on the optical plates. 24 hrs later, cellswere treated with compound for 3 hrs and then incubated with MitotrackerRed CMXRos (50 nM) for 5 min. Cells were washed with PBS for 10 min andfixed with 2% PFA for 30 min at room temperature. Following anotherthree additional washes in PBS, cells were examined with a Nikon A 1-Rconfocal microscope using 488 nm and 561 nm lasers.

Transient Focal Cerebral Ischemia

Transient focal cerebral ischemia was induced by middle cerebral arteryocclusion (MCAO) in rats as described previously, with slightmodifications (Uluc, Miranpuri et al. 2011). Briefly, male SpragueDawley rats (weight 280-320 g) were anesthetized with 2% isoflurane. Theleft common, external, and internal carotid arteries (CCA, ECA, and ICA)were exposed. A 4-0 monofilament nylon suture with a silicon-coated tipwas introduced through an incision of the ECA into the ICA to occludethe origin of the MCA for 1 h. Compound was injected into the leftstriatum after the suture insertion, at the following coordinates inreference to the bregma: AP, 0.4; ML, 3.0; DV, −5.0 mm (from the dura).Solution was injected at a rate of 1 μL/minute using a Hamilton syringe.The syringe was left in place for 5 min before being slowly retracted.Animals were sacrificed 24 h after the MCAO. Brains were removed andsliced into sections of 2 mm thickness. Infarct size was examined viastaining with 1.5% 2, 3, 5-triphenyltetrazolium chloride.

Representative, Exemplary Compounds

Hit.

TABLE 4a SAR optimization:

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

TABLE 4b SAR optimization:

9272

9273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

Compound Preparation

2-(methylsulfinyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine (1)

Step 1. Preparation of 4,4,4-trifluoro-1-(thiophen-2-yl)butane-1,3-dione(1-01)

1-(thiophen-2-yl)ethanone (20 g, 16 mmol) was added to a solution ofNaOMe (10.3 g, 19 mmol) in MeOH at 0° C. dropwise, and the mixture wasstirred at room temperature for 1 hr. Then the mixture was cooled to 0°C., and ethyl 2,2,2-trifluoroacetate (27 g, 19 mmol) was added inportions, and the whole reaction mixture was stirred and refluxed at 80°C. overnight. After the organic solvent was evaporated in vacuo, therisidue was dissolved in H₂O (200 mL), acified by HCl (120 mL, 1N), andextracted by EtOAc (200 mL) 3 times. The organic layer was combined,washed with brine, dried over Na₂SO₄, concentrated and further purifiedby silica gel column chromatography (PE/EA=20/1), to give 11 g of4,4,4-trifluoro-1-(thiophen-2-yl)butane-1,3-dione (1-01) as a light redsolid (32%).

Step 2. Preparation of4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine-2-thiol (1-02)

AcOH (0.8 mL) was added to a solution of4,4,4-trifluoro-1-(thiophen-2-yl)butane-1,3-dione (1 g, 4.5 mmol) andthiourea (1.7 g, 22.5 mmol) in MeOH (4 mL) in a 25 mL microwave tubeunder N₂ atmosphere. The reaction mixture was microwaved at 95° C. for 2hrs. The reaction mixture was filtered. Solvents were removed in vacuofrom the filtrate, then the residue was extracted 3 times with EtOAc andH₂O. The organic layer was combined, washed by brine, dried over Na₂SO₄,then the solvent was evaporated in vacuo. The solid residue was furtherpurified by silica gel column chromatograpy (PE/EA=1/1) to give 0.6 g of4-(thiophen-2-yl)-6-(trifluoromethyl) pyrimidine-2-thiol as an orangesolid (1-02) (50%). ¹H NMR (CDCl₃) δ 7.86 (dd, J=1.2, 4.0 Hz, 1H), 7.63(dd, J=1.2, 5.2 Hz, 1H), 7.51 (s, 1H), 7.20 (dd, J=4.0, 5.2 Hz, 1H).

Step 3. Preparation of2-(methylsulfinyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine (1)

1.1 eq of K₂CO₃(35 mg, 0.25 mmol) was added to a solution of 1-02 (60mg, 023 mmol) and CH₃I (36 mg, 0.25 mmol) in DMF (1 mL), and thereaction mixture was stirred at room temperature for 2 hrs. The reactionmixture was then extracted by EtOAc/H₂O (15 mL/15 mL) 3 times. Theorganic layer was combined, washed with brine, dried over Na₂SO₄,concentrated and further purified by silica gel column chromatography(PE/EA=1/1) to give2-(methylthio)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine as awhite solid.

mCPBA (85 mg, 0.49 mmol) was added to a solution of2-(methylthio)-4-(thiophen-2-yl)-6-(trifluoromethyl) pyrimidine (54 mg,0.196 mmol) in DCM, and the reaction mixture was stirred at roomtemperature for 2 hrs. The reaction mixture was extracted by saturedNaHCO₃/DCM (10 mL/10 mL) 3 times. The organic layer was combined, washedby brine, dried over Na₂SO₄ and further purified silica gel columnchromatography (PE/EA=1/1) to give 1 in a yield of 18% (10 mg, 0.04mmol) as a white solid. Compound 1 ¹H NMR (400 MHz, CDCl₃): δ 8.02 (dd,J=1.2, 4.0 Hz, 1H0, 7.84 (s, 1H), 7.12 (dd, J=1.2, 5.2 Hz, 1H), 7.25(dd, J=4.0, 5.2 Hz, 1H), 3.05 (s, 1H).

2-(ethylsulfonyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine (2)

The titled compound 2 was prepared in a yield of 15% (12 mg, 0.04 mmol)as a light yellow solid from 1-02 (60 mg, 023 mmol) and iodoethane (27mg, 0.25 mmol) according to the procedure for 1. ¹H NMR (400 MHz,DMSO-d₆): δ 8.78 (s, 1H), 8.52 (dd, J=1.2, 4.0 Hz, 1H), 8.11 (dd, J=1.2,4.8 Hz, 1H), 7.38 (dd, J=4.0, 4.8 Hz, 1H), 3.67 (q, J=7.2 Hz, 2H), 1.34(t, J=7.2 Hz, 3H).

2-(ethylsulfinyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine (3)

The titled compound 3 was prepared in a yield of 24% (18 mg, 0.06 mmol)as a light yellow solid from 1-02 (60 mg, 023 mmol) and iodoethane (27mg, 0.25 mmol) according to the procedure for TC009014. ¹H NMR (400 MHz,CDCl₃): δ 8.02 (dd, J=1.2, 3.6 Hz, 1H), 7.82 (s, 1H), 7.71 (dd, J=1.2,4.8 Hz, 1H), 7.25 (dd, J=3.6, 4.8 Hz, 1H, 3.26-3.35 (m, 1H), 3.14-3.24(m, 1H), 1.34 (t, J=7.2 Hz, 3H). LC-MS (ESI) m/z: calcd for[C11H10F3N2OS2+], 307.0, found 307.3.

2-(propylsulfonyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine (4)

The titled compound 4 was prepared in a yield of 25% (19 mg, 0.06 mmol)as a light yellow solid from 1-02 (60 mg, 0.23 mmol) and 1-iodopropane(30 mg, 0.25 mmol) according to the procedure for 1. ¹H NMR (400 MHz,DMSO-dd): δ 8.78 (s, 1H), 8.52 (d, J=3.6 Hz, 1H), 8.11 (d, J=4.8 Hz,1H), 7.36-7.39 (m, 1H), 3.62-3.67 (m, 2H), 1.77-1.87 (m, 2H), 1.04 (t,J=7.2 Hz, 3H). LC-MS (ESI) m/z: calcd for [C₁₂H₁₂F₃N₂O₂S₂ ⁺], 337.0,found 337.2.

2-(propylsulfinyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine (5)

The titled compound 5 was prepared in a yield of 19% (14 mg, 0.04 mmol)as a light yellow solid from 1-02 (60 mg, 0.23 mmol) and 1-iodopropane(30 mg, 0.25 mmol) according to the procedure for 1. LC-MS (ESI) m/z:calcd for [C₁₂H₁₂F₃N₂OS₂ ⁺], 321.0, found 321.4.

2-(prop-2-yn-1-ylsulfonyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine (6)

The titled compound 6 was prepared in a yield of 48% (120 mg, 0.36 mmol)as a white solid from 1-02 (200 mg, 0.76 mmol) and 3-bromoprop-1-yne(100 mg, 0.95 mmol) according to the procedure for 1. ¹H NMR (400 Hz,CDCl3) δ 8.05 (dd, J=1.2, 4.0 Hz, 1H), 7.95 (s, 1H), 7.77 (dd, J=1.2,5.2 Hz, 1H), 7.27 (dd, J=4.0, 5.2 Hz, 1H), 4.52 (d, J=2.8 Hz, 2H), 3.92(t, J=2.8 Hz, 1H). LC-MS (ESI) m/z: calcd for [C₁₂H₈F₃N₂O₂S₂ ⁺], 333.0,found 333.2.

2-(phenylsulfinyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine (7)

The titled compound 7 was prepared in a yield of 12%(10 mg, 0.03 mmol)as a light yellow solid from 1-02 (60 mg, 0.23 mmol) and 1-iodobenzene(51 mg, 0.25 mmol) according to the procedure for TC009014. ¹H NMR (400MHz, DMSO-d₆): δ 8.69 (s, 1H), 8.438 (dd, J=1.2, 4.0 Hz, 1H), 8.06-8.09(m, 2H), 8.05 (dd, J=1.2, 4.0 Hz, 1H), 7.83-7.86 (m, 1H), 7.73-7.76 (m,2H), 7.33 (dd, J=4.0, 4.8 Hz, 1H).

2-chloro-6-(4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-ylsulfinyl)pyrazine(8)

The titled compound 8 was prepared in a yield of 8%(7 mg, 0.02 mmol) asa light yellow solid from 1-02 (60 mg, 0.23 mmol) and 1-iodobenzene2,6-dichloropyrazine (37 mg, 0.25 mmol) according to the procedurefor 1. ¹H NMR (400 MHz, DMSO-d₆): δ 9.11 (s, 1H), 8.93 (s, 1H),8.332-8.35 (m, 1H), 8.30 (s, 1H), 7.96 (dd, J=1.2, 4.8 Hz, 1H), 7.29(dd, J=4.8 Hz, 1H).

2-((cyclopropylmethyl)sulfonyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine(9)

The titled compound 9 was prepared in a yield of 12%(7 mg, 0.02 mmol) asa white solid from 1-02 (50 mg, 0.19 mmol) and (bromomethyl)cyclopropane(46 mg, 0.21 mmol) according to the procedure for 1. ¹H NMR (400 Hz,CDCl₃) δ8.03 (d, J=3.6 Hz, 1H), 7.93 (s, 1H), 7.74 (d, J=4.8 Hz, 1H),7.25 (m. 1H), 3.56 (d, J=7.2 Hz, 2H), 0.83-0.89 (m, 1H), 0.65-0.71 (m,2H), 0.40-0.45 (m, 2H).

2-((cyclopropylmethyl)sulfinyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine(10)

The titled compound 10 was prepared in a yield of 8%(4.3 mg, 0.013 mmol)as a white solid from 1-02 (50 mg, 0.19 mmol) and(bromomethyl)cyclopropane (46 mg, 0.21 mmol) according to the procedurefor 1. ¹H NMR (400 Hz, CDCl₃) δ8.01 (d, J=3.6 Hz, 1H), 7.82 (s, 1H),7.71 (d, J=4.8 Hz, 1H), 7.24 (m, 1H), 3.08-3.18 (m, 2H), 0.86-0.89 (m,1H), 0.68-0.74 (m, 1H), 0.61-0.66 (m, 1H). 0.35-0.42 (m, 1H), 0.23-0.28(m, 1H).

2-(benzylsulfonyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine (11)

The titled compound 11 was prepared in a yield of 25% (19 mg, 0.06 mmol)as a light yellow solid from 1-02 (60 mg, 0.23 mmol) and1-(bromomethyl)benzene (43 mg, 0.25 mmol) according to the procedurefor 1. ¹H NMR (400 MHz, DMSO-d₆): δ 8.78 (s, 1H), 8.53 (dd, J=1.2, 4.0Hz, 1H), 8.13 (dd, J=1.2, 4.8 Hz, 1H), 7.32-7.42 (m, 6H), 5.05 (s, 2H).

2-(benzylsulfinyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine (12)

The titled compound 12 was prepared in a yield of 11%(9 mg, 0.03 mmol)as a light yellow solid from 1-02 (60 mg, 0.23 mmol) and1-(bromomethyl)benzene (43 mg, 0.25 mmol) according to the procedurefor 1. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (dd, J=0.8, 4.0 Hz, 1H), 7.77 (s,1H), 7.71 (dd, J=0.8, 4.8 Hz, 1H), 7.25-7.28 (m, 3H), 7.24 (dd, J=4.0,4.8 Hz, 1H), 7.18-7.21 (m, 2H), 4.47 (d, J=13.2 Hz, 1H), 4.34 (d, J=13.2Hz, 1H).

2-(((4-(thiophen-2-yl)-6-(trifluoromethyl) pyrimidin-2-yl) sulfonyl)methyl) benzonitrile (13)

The titled compound 13 was prepared in a yield of 10%(8 mg, 0.02 mmol)as a white solid from 1-02 (50 mg, 0.19 mmol) and2-(bromomethyl)benzonitrile (29 mg, 0.21 mmol) according to the theprocedure for 1. ¹H NMR (400 Hz, CDCl₃) δ 8.05 (dd, J=0.8, 4.0 Hz, 1H),7.94 (s, 1H), 7.75-7.79 (m, 2H), 7.72 (dd, J=0.8, 7.6 Hz, 1H), 7.62-7.67(m, 1H), 7.48-7.53 (m, 1H), 7.25-7.27 (m, 1H), 5.10 (s, 2H).

2-(((4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-yl)sulfinyl)methyl)benzonitrile (14)

The titled compound 14 was prepared in a yield of 8%(6 mg, 0.02 mmol) asa white solid from 1-02 (50 mg, 0.19 mmol) and2-(bromomethyl)benzonitrile (29 mg, 0.21 mmol) according to the theprocedure for 1. ¹H NMR (400 Hz, CDCl₃) δ 7.99 (dd, J=0.8, 4.0 Hz, 1H),7.84 (s, 1H), 7.71 (dd, J=0.8, 4.8 Hz, 1H), 7.54-7.63 (m, 3H), 7.41-7.46(m, 1H), 7.24 (dd, J=4.0, 4.8 Hz, 1H), 4.73 (d, J=13.2 Hz, 1H), 4.53 (d,J=13.2 Hz, 1H).

3-(((4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-yl)sulfinyl)methyl)benzonitrile (15)

The titled compound 15 was prepared in a yield of 20% (17 mg, 0.03 mmol)as a white solid from 1-02 (60 mg, 0.23 mmol) and3-(bromomethyl)benzonitrile (49 mg, 0.26 mmol) according to the theprocedure for 1. ¹H NMR (400 Hz, CDCl₃) δ 7.99 (d, J=4.0, 1H), 7.81 (s.1H), 7.74 (d, J=4.8, 1H), 7.57 (d, J=7.6, 1H), 7.51 (d, J=7.6, 1H), 7.44(s, 1H), 7.41 (t, J=7.6, 1H), 7.24 (dd, J=4.0, 4.8 Hz, 1H), 4.48 (d,J=13.2 Hz, 1H), 4.38 (d, J=13.2 Hz, 1H).

2-((3-methoxybenzyl)sulfinyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine(16)

The titled compound 16 was prepared in a yield of 51% (47 mg, 0.12 mmol)as a white solid from 1-02 (60 mg, 0.23 mmol) and1-(chloromethyl)-3-methoxybenzene (40 mg, 0.26 mmol) according to thethe procedure for 1. ¹H NMR (400 Hz, CDCl₃) δ 7.98 (d, J=3.2 Hz, 1H),7.78 (s, 1H), 7.71 (d, J=4.8 Hz, 1H), 7.24 (dd, J=4.0, 4.8 Hz, 1H), 7.18(t, J=8.0 Hz, 1H), 6.82-6.78 (3, 3H), 4.44 (d, J=12.8 Hz, 2H), 4.32 (d,J=12.8 Hz, 2H), 3.74 (s, 3H).

2-((4-methoxybenzyl)sulfinyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine(17)

The titled compound 17 was prepared in a yield of 45% (43 mg, 0.11 mmol)as a white solid from 1-02 (60 mg, 0.23 mmol) and1-(chloromethyl)-4-methoxybenzene (40 mg, 0.26 mmol) according to thethe procedure for 1. ¹H NMR (400 Hz, CDCl₃) δ 7.98 (d, J=3.6 Hz, 1H),7.77 (s, 1H), 7.71 (d, J=5.2 Hz, 1H), 7.24 (t, J=4.4 Hz, 1H), 7.11 (d,J=8.8 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 4.42 (d, J=13.2 Hz, 1H), 4.30 (d,J=13.2 Hz, 1H), 3.74 (s, 3H).

2-((3,5-difluorobenzyl)sulfonyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine(18)

The titled compound 18 was prepared in a yield of 12%(9 mg, 0.02 mmol)as a white solid from 1-02 (50 mg, 0.19 mmol) and1-(bromomethyl)-3,5-difluorobenzene (29 mg, 0.21 mmol) according to theprocedure for 1. ¹H NMR (400 Hz, CDCl₃) δ 8.03 (dd, J=0.8, 4.0 Hz, 1H),7.92 (s, 1H), 7.77 (dd, J=0.8, 4.8 Hz, 1H), 7.27 (dd, J=4.0, 4.8 Hz,1H), 7.04-7.07 (m, 2H), 6.76-6.82 (m, 1H), 4.86 (s, 2H).

2-((3,5-difluorobenzyl)sulfinyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine(19)

The titled compound 19 was prepared in a yield of 10%(8 mg, 0.02 mmol)as a white solid from 1-02 (50 mg, 0.19 mmol) and1-(bromomethyl)-3,5-difluorobenzene (29 mg, 0.21 mmol) according to theprocedure for 1. ¹H NMR (400 Hz, CDCl3) δ 8.00 (dd, J=0.8, 4.0 Hz, 1H),7.81 (s, 1H), 7.73 (dd, J=0.8, 4.8 Hz, 1H), 7.25 (dd, J=4.0, 4.8 Hz,1H), 6.71-6.80 (m, 3H), 4.43 (d, J=13.2 Hz, 1H), 4.29 (d, J=13.2 Hz,1H).

2-(([1,1′-biphenyl]-4-ylmethyl)sulfinyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine (20)

The titled compound 20 was prepared in a yield of 12%(12 mg, 0.03 mmol)as a light yellow solid from 1-02 (60 mg, 0.23 mmol) and4-(chloromethyl)-1,1′-biphenyl (51 mg, 0.25 mmol) according to theprocedure for 1. ¹H NMR (400 MHz, DMSO-d₆): δ 8.79 (s, 1H), 8.54 (dd,J=1.2, 4.0 Hz, 1H), 8.13 (dd, J=1.2, 5.2 Hz, 1H), 7.64-7.68 (m, 4H),7.48-7.52 (m, 2H), 7.43-7.48 (m, 2H), 7.36-7.40 (m, 2H)

4-(4-(((4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-yl)sulfinyl)methyl)phenyl)morpholine4-oxide (21)

To a solution of 1-02 (75 mg, 0.28 mmol) and(4-morpholinophenyl)methanol (50 mg, 0.26 mmol) in dry THF (1.7 mL) wasadded PPh₃(88 mg, 0.31 mmol) and DIAD (70 mg, 0.34 mmol) in portionsunder N₂ atmosphere at 0° C. The reaction mixture was stirred at 0° C.for 8 hrs. The reaction mixture was raised to room temperature, thensolvents were removed in vacuo. The residue was extracted by DCM/H₂O 3times. The organic layer was washed by brine, dried over Na₂SO₄ andfurther purified by silica gel column chromatography (PE/EA=1/1) to give2-((4-(piperazin-1-yl)benzyl)thio)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidineas a white solid (90%).

The titled compound 21 was prepared in a yield of 87%(94 mg, 0.20 mmol)as a white solid from2-((4-(piperazin-1-yl)benzyl)thio)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine(100 mg, 0.23 mmol) and mCPBA (50 mg, 0.29 mmol) according to thegeneral procedure for 1. ¹H NMR (400 Hz, CDCl3) δ 7.96 (dd, J=0.8, 4.0Hz, 1H), 7.88-7.92 (m, 2H), 7.76 (s, 1H), 7.71 (dd, J=0.8, 4.8 Hz, 1H),7.29-7.33 (m, 2H), 7.24 (dd, J=4.0, 4.8 Hz, 1H), 4.61-4.70 (m, 2H), 4.49(d, J=13.2 Hz, 1H), 4.38 (d, J=13.2 Hz, 1H), 3.77-3.92 (m, 4H),2.91-3.08 (m, 2H). LC-MS (ESI) m/z: calcd for [C₂₀H₁₉F₃N₃O₃S₂ ⁺], 470.1,found 470.2.

4-(4-(((4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-yl)sulfonyl)methyl)phenyl)morpholine4-oxide (22)

The titled compound 22 was prepared in a yield of 81%(150 mg, 0.31 mmol)as a white solid from 1-02 (113 mg, 0.42 mmol) and(4-morpholinophenyl)methanol (75 mg, 0.39 mmol) according to the generalprocedure for 1. ¹H NMR (400 Hz, CDCl3) δ 8.02 (dd, J=0.8, 4.0 Hz, 1H),8.01˜7.98 (m, 2H), 7.91 (s, 1H), 7.77 (dd, J=0.8, 5.2 Hz, 1H), 7.66˜7.63(m, 2H), 7.24 (dd, J=4.0, 5.2 Hz, 1H), 4.94 (s, 2H), 4.72˜4.66 (m, 2H),3.92˜3.85 (m, 4H), 3.14˜3.09 (m, 2H). LC-MS (ESI) m/z: calcd for[C₂₀H₁₉F₃N₃O₄S₂ ⁺], 486.1, found 486.2.

6-(((4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-yl)sulfonyl)methyl)quinoline 1-oxide (23)

The titled compound 23 was prepared in a yield of 23%(62 mg, 0.14 mmol)as a white solid from 1-02 (158 mg, 0.61 mmol) and6-(bromomethyl)quinoline (150 mg, 0.67 mmol) according to the procedurefor 1. ¹H NMR (400 Hz, DMSO) δ 8.78 (s, 1H), 8.59 (d, J=6 Hz, 1H),8.53-8.49 (m, 2H), 8.16 (s, 1H), 8.12 (d, J=5.2 Hz, 1H), 7.90 (d, J=8.4Hz, 1H), 7.85 (dd, J=2, 8.4 Hz, 1H), 7.48 (dd, J=6, 8.4 Hz, 1H), 7.38(t, J=4.4 Hz, 1H), 5.31 (s, 2H). LC-MS (ESI) m/z: calcd for[C₁₉H₁₃F₃N₃O₃S₂ ⁺], 452.0, found 452.2.

6-(((4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-yl)sulfinyl)methyl)quinoline (24)

The titled compound 24 was prepared in a yield of 10% (11 mg, 0.03 mmol)as a white solid from 1-02 (70 mg, 0.27 mmol) and6-(bromomethyl)quinoline (65 mg, 0.29 mmol) according to the procedurefor 1. ¹H NMR (400 MHz, DMSO-d₆): δ 8.86-8.88 (m, 1H), 8.56 (s, 1H),8.44-8.50 (m, 1H), 8.25-8.28 (m, 1H), 8.03 (dd, J=4.0, 4.8 Hzm 1H), 7.89(d, J=13.2 Hz, 1H), 7.76 (s, 1H), 7.46-7.52 (m, 2H), 7.34 (dd, J=3.6,4.8 Hz, 1H), 4.73 (d, J=13.2Hzm 1H), 4.60 (d, J=13.2 Hz, 1H). LC-MS(ESI) m/z: calcd for [C₁₉H₁₃F₃N₃OS₂ ⁺], 420.0, found 420.1.

1-(2-((4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-yl)sulfinyl)ethyl)pyrrolidin-2-one (25)

The titled compound 25 was prepared in a yield of 11% (10 mg, 0.02 mmol)as a light yellow solid from 1-02 (60 mg, 0.23 mmol) and1-(2-chloroethyl)pyrrolidin-2-one (37 mg, 0.25 mmol) according to thethe procedure for 1. ¹H NMR (400 MHz, DMSO-d₆): δ 8.80 (s, 1H), 8.54(dd, J=1.2, 4.0 Hz, 1H), 8.12 (dd, J=1.2, 5.2 Hz, 1H), 7.38 (dd, J=4.0,5.2 Hz, 1H), 3.91 (t, J=6.8 Hz, 2H), 3.71 (t, J=4.8 Hz, 2H), 3.38 (t,J=6.8 Hz, 2H), 2.08 (t, J=8.0 Hz, 2H), 1.77-1.86 (m, 2H).

2-(phenethylsulfonyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine(26)

The titled compound 26 was prepared in a yield of 8%(6 mg, 0.015 mmol)as a white solid from 1-02 (50 mg, 0.19 mmol) and (2-bromoethyl)benzene(39 mg, 0.21 mmol) according to the procedure for 1. ¹H NMR (400 Hz,CDCl₃) δ 7.98 (dd, J=0.8, 4.0 Hz, 1H), 7.84 (s, 1H), 7.74 (dd, J=0.8,4.8 Hz, 1H), 7.24 (dd, J=4.0, 4.8 Hz, 1H), 7.12-7.21 (m, 5H), 3.87-3.92(m, 2H), 3.21-3.27 (m, 2H).

2-(phenethylsulfinyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine(27)

The titled compound 27 was prepared in a yield of 10% (7 mg, 0.02 mmol)as a white solid from 1-02 (50 mg, 0.19 mmol) and (2-bromoethyl)benzene(39 mg, 0.21 mmol) according to the procedure for 1. ¹H NMR (400 Hz,CDCl₃) δ 7.96 (dd, J=0.8, 4.0 Hz, 1H), 7.71 (s, 1H), 7.69 (dd, J=0.8,4.8 Hz, 1H), 7.11-7.25 (m, 6H), 3.49-3.54 (m, 2H), 3.18-3.27 (m, 1H),3.02-3.10 (m, 1H).

3-((4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-yl)sulfinyl)propanoicacid (28)

The titled compound 28 was prepared in a yield of 18% as a white solidfrom 1-02 (25 mg, 0.09 mmol) and 3-chloropropanoic acid (11 mg, 0.10mmol) according to the procedure for 1. ¹H NMR (400 Hz, CDCl3) δ 12.40(br, 1H), 8.57 (s, 1H), 8.44 (d, J=3.2 Hz, 1H), 8.02 (d, J=4.4 Hz, 1H),7.32 (dd, 0.1=3.2, 4.4 Hz, 1H), 3.53-3.46 (m, 1H), 3.28-3.21 (m, 1H),2.76-2.61 (m, 2H).

Ethyl3-((4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-yl)sulfonyl)propanoate(29)

The titled compound 29 was prepared in a yield of 36% as a white solidfrom 1-02 and ethyl 3-chloropropanoate according to the procedure for 1.¹H NMR (400 Hz, CDCl₃) δδ8.03 (dd. J=1.2, 4.0 Hz, 1H), 7.94 (s, 1H),7.75 (dd, J=1.2, 4.8 Hz, 1H), 7.26 (dd, J=4.0, 4.8 Hz, 1H), 4.17 (q,J=7.2 Hz, 2H), 3.95 (t, J=7.6 Hz, 2H), 3.01 (t, J=7.6 Hz, 2H), 1.27 (t,J=7.2 Hz, 3H).

ethyl 3-((4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-yl)sulfinyl)propanoate (30)

The titled compound 30 was prepared in a yield of 26%(90 mg, 0.24 mmol)as a white solid from 1-02 (100 mg, 0.38 mmol) and ethyl3-chloropropanoate (57 mg, 0.42 mmol) according to the procedure for 1.¹H NMR (400 Hz, CDCl₃) δ 8.01 (dd, J=0.8, 3.6 Hz, 1H), 7.83 (s, 1H),7.72 (dd, J=0.8, 4.8 Hz, 1H), 7.25 (dd, J=3.6, 4.8 Hz, 1H), 4.09 (m,2H), 3.59 (m, 1H), 3.42 (m, 1H), 3.00 (m, 1H), 2.77 (m, 1H), 1.22 (t,J=7.2 Hz, 3H).

methyl 4-((4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-yl)sulfonyl)butanoate (31)

The titled compound 31 (30 mg, 0.08 mmol) was prepared in a yield of 20%as a white solid from 1-02 (76 mg, 0.28 mmol) and methyl4-chlorobutanoate (39 mg, 0.32 mmol) according to the procedure for 1.¹H NMR (400 Hz, CDCl₃) δ 8.04 (dd, J=0.8, 4.0 Hz, 1H), 7.94 (s, 1H),7.76 (dd, J=0.8, 5.2 Hz, 1H), 7.26 (dd, J=4.0, 5.2 Hz, 1H), 3.70-3.74(m, 2H), 3.69 (s, 3H), 2.60 (t, J=7.2 Hz, 2H), 2.24-2.33 (m, 2H).

methyl 4-((4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-yl)sulfinyl)butanoate (32)

The titled compound 32 (60 mg, 0.158 mmol) was prepared in a yield of38% as a white solid from 1-02 (76 mg, 0.28 mmol) and methyl4-chlorobutanoate (39 mg, 0.32 mmol) according to the procedure for 1.¹H NMR (400 Hz, CDCl₃) δ 8.00 (dd, J=0.8, 4.0 Hz, 1H), 7.83 (s, 1H),7.68 (dd, J=0.8, 5.2 Hz, 1H), 7.21 (dd, J=4.0, 5.2 Hz, 1H), 3.60 (s,3H), 3.15-3.32 (m, 2H), 2.48-2.51 (m, 2H), 2.21-2.31 (m, 1H), 1.98-2.08(m, 1H).

4-chloro-2-(methylsulfonyl)-6-(thiophen-2-yl)pyrimidine (33)

Step 1. Preparation of4-chloro-2-(methylthio)-6-(thiophen-2-yl)pyrimidine (33-01)

To a solution of 4,6-dichloro-2-(methylthio)pyrimidine (400 mg, 2.06mmol) and thiophen-2-ylboronic acid (300 mg, 2.26 mmol) in DME/H₂O (4mL/2 mL) was added Pd(PPh₃)₄ (69 mg, 0.06 mmol) and Na₂CO₃ (546 mg, 4.12mmol) in portions under N₂ atmosphere. The reaction mixture was heatedand refluxed for 2 hrs. The reaction mixture was cooled to roomtemperature, and filtered over celite. Solvent was evaporated in vacuo,and the residue was extracted by EtOAc/H₂O (30 ml/30 mL) 3 times. Theorganic layer was combined, washed by brine, dried over Na₂SO₄, andfurther purified by silica gel column chromatography (PE/EA=20/1) togive 112 mg of 4-chloro-2-(methylthio)-6-(thiophen-2-yl)pyrimidine(33-01) as a white solid (27%). ¹H NMR (400 Hz, CDCl₃) δ 7.76 (dd,J=0.8, 4.0 Hz, 1H), 7.56 (dd, J=0.8, 4.8 Hz, 1H), 7.72 (s, 1H), 7.16(dd, J=4.0, 4.8 Hz, 1H), 2.62 (s, 3H).

Step 2. Preparation of 33

mCPBA (15 mg, 0.09 mmol) was added to a solution of 33-01(30 mg, 0.09mmol) in DCM and the reaction mixture was stirred at room temperaturefor 2 hrs. The reaction mixture was extracted by DCM and satured NaHCO₃solution 3 times. The organic layer was combined, washed with brine,dried over Na₂SO₄ and further purified by silica gel columnchromatography (PE/EA=1/1) to give 25 mg of4-chloro-2-(methylsulfinyl)-6-(thiophen-2-yl) pyrimidine as a whitesolid (78%). ¹H NMR (400 Hz, CDCl3) δ 7.90 (dd, J=0.8, 3.6 Hz, 1H), 7.64(dd, J=1.2, 4.8 Hz, 1H), 7.57 (s, 1H), 7.19 (dd, J=3.6, 4.8 Hz, 1H),3.00 (s, 3H). LC-MS (ESI) m/z: calcd for [C₉H₈ClN₂OS⁺], 259.0, found259.1.

4-methyl-2-(methylsulfonyl)-6-(thiophen-2-yl)pyrimidine (34)

To a solution of 4-chloro-2-(methylthio)-6-(thiophen-2-yl)pyrimidine(33-01)(70 mg, 0.29 mmol) in THF/NMP (2 mL/0.4 mL) was added Fe(acac)₃(6mg, 0.01 mmol) followed by CH₃MgCl (30 mg, 0.35 mmol) dropwise at −20°C. under N₂ atmosphere. The reaction mixture was stirred at −20° C. toroom temperature overnight. The reaction mixture was filtered, andsolvents were removed from the filtrate in vacuo. The residue wasextracted by EtOAc/H₂O 3 times. The organic layer was washed with brine,dried over Na₂SO₄ and further purified by silica gel columnchromatography (PE/EA=10/1) to give 12 mg of4-methyl-2-(methylthio)-6-(thiophen-2-yl) pyrimidine as a light yellowoil (20%).

mCPBA (24 mg, 0.14 mmol) was added to a solution of4-methyl-2-(methylthio)-6-(thiophen-2-yl) pyrimidine (12 mg, 0.05 mmol)in DCM and the reaction mixture was stirred at room temperature for 2hrs. The reaction mixture was extracted by DCM and satured NaHCO₃solution 3 times. The organic layer was combined, washed with brine,dried over Na₂SO₄ and further purified by silica gel columnchromatography (PE/EA=1/1) to give 2 mg of4-methyl-2-(methylsulfonyl)-6-(thiophen-2-yl) pyrimidine as a whitesolid (14%). LC-MS (ESI) m/z: calcd for [C₁₀H₁₁N₂O₂S₂ ⁺], 255.0, found255.1.

4-ethynyl-2-(methylsulfonyl)-6-(thiophen-2-yl)pyrimidine (35)

Step 1. Preparation of 4-ethynyl-2-(methylthio)-6-(thiophen-2-yl)(35-01)

Pd(PPh₃)₂Cl₂ (1.2 mg, 0.002 mmol) and CuI (1 mg, 0.005 mmol) was addedto as solution of 4-chloro-2-(methylthio)-6-(thiophen-2-yl)pyrimidine(33-01)(40 mg, 0.16 mmol) in THF/TEA (1 mL/1.5 mL) under N₂ atmosphere,followed by the addition of ethynyltrimethylsilane(18 mg, 0.18 mmol)dropwise. The reaction mixture was refluxed at 60° C. for 8 hrs. Thereaction mixture was cooled to room temperature and filtered overcelite. Solvents was evaporated in vacuo, and the residue was dissolvedin dry DCM at room temperature, followed by the addition of TBAF (47 mg,0.18 mmol). The reaction mixture was stirred at room temperature for 3hrs. Then the reaction mixture was extracted by DCM/H₂O 3 times. Theorganic layer was combined, washed with brine, dried over Na₂SO₄ andfurther purified by silica gel column chromatography (PE/EA=10/1) togive 12 mg of 4-ethynyl-2-(methylthio)-6-(thiophen-2-yl) pyrimidine as awhite solid (31%).

Step 2. Preparation of 35

mCPBA (35 mg, 0.20 mmol) was added to a solution of 35-01(12 mg, 0.05mmol) in DCM and the reaction mixture was stirred at room temperaturefor 2 hrs. The reaction mixture was extracted by DCM and satured NaHCO₃solution 3 times. The organic layer was combined, washed with brine,dried over Na₂SO₄ and further purified by silica gel columnchromatography (PE/EA=1/1) to give 5 mg of4-ethynyl-2-(methylsulfonyl)-6-(thiophen-2-yl) pyrimidine as a whitesolid (37%). ¹H NMR (400 Hz, CDCl3) δ 7.92 (dd, J=0.8, 4.0 Hz, 1H), 7.75(s, 1H), 7.67 (dd, J=1.2, 4.8 Hz, 1H), 7.21 (dd, J=4.0, 4.8 Hz, 1H),3.53 (s, 1H), 3.40 (s, 3H). LC-MS (ESI) m/z: calcd for [C₁₁H₉N₂O₂S₂ ⁺],265.0, found 265.2.

2-(methylsulfonyl)-4-(1H-pyrazol-1-yl)-6-(thiophen-2-yl)pyrimidine (36)

K₂CO₃ (34 mg, 0.25 mmol) was added to a solution of4-chloro-2-(methylthio)-6-(thiophen-2-yl)pyrimidine (51-01)(30 mg, 0.13mmol) and 1H-pyrazole (12 mg, 0.18 mmol) in DMF. The reaction mixturewas microwaved at 100° C. for 2 hrs. The reaction mixture was cooled toroom temperature, and extracted by EtOAc/H₂O 3 times. The organic layerwas combined, washed with brine, dried over Na₂SO₄ and further purifiedby silica gel column chromatography (PE/EA=10/1) to give 16 mg of2-(methylthio)-4-(1H-pyrazol-1-yl)-6-(thiophen-2-yl)pyrimidine as awhite solid (47%).

mCPBA (30 mg, 0.17 mmol) was added to a solution of2-(methylthio)-4-(1H-pyrazol-1-yl)-6-(thiophen-2-yl)pyrimidine (16 mg,0.06 mmol) in DCM and the reaction mixture was stirred at roomtemperature for 2 hrs. The reaction mixture was extracted by DCM andsatured NaHCO₃ solution 3 times. The organic layer was combined, washedwith brine, dried over Na₂SO₄ and further purified by silica gel columnchromatography (PE/EA=1/1) to give 5 mg of2-(methylsulfonyl)-4-(1H-pyrazol-1-yl)-6-(thiophen-2-yl) pyrimidine as awhite solid (28%). ¹H NMR (400 Hz, CDCl3) δ 8.67 (d, J=0.8 Hz, 1H), 8.24(s, 1H), 7.98 (dd, J=0.8, 4.0 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.64 (dd,J=0.8, 5.2 Hz, 1H), 7.21 (dd, J=4.0, 5.2 Hz, 1H), 6.56 (dd, J=1.6, 2.8Hz, 1H), 3.45 (s, 3H). LC-MS (ESI) m/z: calcd for [C₁₂H₁₁N₄O₂S₂ ⁺],307.0, found 307.2.

2-(methylsulfonyl)-4,6-di(thiophen-2-yl)pyrimidine (37)

To a solution of 4,6-dichloro-2-(methylthio)pyrimidine (300 mg, 1.54mmol) and thiophen-2-ylboronic acid (800 mg, 6.19 mmol) in DME/H₂O (4mL/2 mL) was added Pd(PPh₃)₄ (56 mg, 0.05 mmol) followed by Na₂CO₃ (655mg, 6.19 mmol) under N₂ atmosphere. The reaction mixture was microwavedat 150° C. for 2 hrs. The reaction mixture was cooled to roomtemperature, and filtered over celite. Solvent was evaporated in vacuo,and the residue was extracted by EtOAc and H₂O 3 times. The organiclayer was combined, washed by brine, dried over Na₂SO₄, and furtherpurified by silica gel column chromatography (PE/EA=100/1) to give 110mg of 2-(methylthio)-4,6-di(thiophen-2-yl)pyrimidine as a white solid(30%).

mCPBA (32 mg, 0.19 mmol) was added to a solution of2-(methylthio)-4,6-di(thiophen-2-yl)pyrimidine (27 mg, 0.09 mmol) in DCMand the reaction mixture was stirred at room temperature for 2 hrs. Thereaction mixture was extracted by DCM and satured NaHCO₃ solution 3times. The organic layer was combined, washed with brine, dried overNa₂SO₄ and further purified by silica gel column chromatography(PE/EA=1/1) to give 6 mg of2-(methylsulfonyl)-4,6-di(thiophen-2-yl)pyrimidine as a white solid(20/%). ¹H NMR (400 Hz, DMSO) δ8.67 (s, 1H), 8.37 (d, J=3.6 Hz, 2H),7.99 (d, J=4.8 Hz, 2H), 7.35 (dd, J=3.6, 4.8 Hz, 2H), 3.46 (s, 3H).LC-MS (ESI) m/z: calcd for [C₁₃H₁₁N₂O₂S₃ ⁺], 323.0, found 323.4.

1-(2-(methylsulfonyl)-6-(thiophen-2-yl)pyrimidin-4-yl)pyrrolidin-2-one(38)

To a solution of 4-chloro-2-(methylthio)-6-(thiophen-2-yl)pyrimidine(33-01)(30 mg, 0.12 mmol) and pyrrolidin-2-one (21 mg, 0.24 mmol) in drydioxane was added binap (8 mg, 0.01 mmol), Pd₂(dba)₃(6 mg, 0.006 mmol)and K₃PO₄(65 mg, 0.30 mmol) under N₂ atmosphere. The reaction wasrefluxed at 160° C. for 8 hrs. The reaction mixture was cooled to roomtemperature, filtered over celite. Solvents were removed from thefiltrate in vacuo, then the residue was extracted by EtOAc/H₂O 3 times.The organic layer was combined, washed with brine, dried over Na₂SO₄ andfurther purified by silica gel column chromatography (PE/EA=4/1) to give12 mg of1-(2-(methylthio)-6-(thiophen-2-yl)pyrimidin-4-yl)pyrrolidin-2-one as ayellow oil (33%).

mCPBA (20 mg, 0.12 mmol) was added to a solution of1-(2-(methylthio)-6-(thiophen-2-yl)pyrimidin-4-yl)pyrrolidin-2-one (12mg, 0.04 mmol) in DCM and the reaction mixture was stirred at roomtemperature for 2 hrs. The reaction mixture was extracted by DCM andsatured NaHCO₃ solution 3 times. The organic layer was combined, washedwith brine, dried over Na₂SO₄ and further purified by silica gel columnchromatography (PE/EA=1/1) to give 2 mg of1-(2-(methylsulfonyl)-6-(thiophen-2-yl) pyrimidin-4-yl) pyrrolidin-2-oneas a white solid (15%). ¹H NMR (400 Hz, CDCl3) δ 8.33 (s, 1H), 7.91 (d,J=4.0 Hz, 1H), 7.58 (d, J=4.8 Hz, 1H), 7.17-7.20 (m, 1H), 4.20 (t, J=7.2Hz, 2H), 3.40 (s, 3H), 2.73 (t, J=8.0 Hz, 2H), 2.16-2.24 (m, 2H).

1-(2-(methylsulfonyl)-6-(thiophen-2-yl)pyrimidin-4-yl)pyridine-2(1H)-one(39)

The titled compound was prepared in a yield of 55% (19 mg, 0.07 mmol) asa white solid from 4-chloro-2-(methylthio)-6-(thiophen-2-yl)pyrimidine(33-01) (30 mg, 0.12 mmol) and pyridin-2(1H)-one (20 mg, 0.15 mmol)according to the procedure for 36. ¹H NMR (400 Hz, DMSO) δ8.72 (s, 1H),8.25 (dd, J=1.2, 4.0 Hz, 1H), 8.09 (dd, J=1.2, 7.2 Hz, 1H), 8.04 (dd,J=1.2, 4.8 Hz, 1H), 7.62 (ddd, J=2.0, 7.6, 9.4 Hz, 1H), 7.34 (dd, J=4.0,4.8 Hz, 1H), 6.62 (d, J=9.2 Hz, 1H), 6.51 (td, J=7.2, 1.2 Hz, 1H), 3.50(s, 3H). LC-MS (ESI) m/z: calcd for [C₁₄H₁₂N₃O₃S₂ ⁺], 334.0, found334.2.

4-(2-(methylsulfonyl)-6-(thiophen-2-yl)pyrimidin-4-yl)morpholine (40)

The titled compound 40 was prepared in a yield of 13%(5 mg, 0.02 mmol)as a white solid from4-chloro-2-(methylthio)-6-(thiophen-2-yl)pyrimidine (33-01) (30 mg, 0.12mmol) and morpholine (15 mg, 0.17 mmol) according to the procedure for53. ¹H NMR (400 Hz, CDCl3) δ 7.76 (dd, J=1.2, 4.0 Hz, 1H), 7.51 (dd,J=1.2, 5.2 Hz, 1H), 7.14 (dd, J=4.0, 5.2 Hz, 1H), 6.78 (s, 1H),3.83-3.73 (m, 8H), 3.35 (s, 3H).

4-azido-2-(methylsulfonyl)-6-(thiophen-2-yl)pyrimidine (41)

NaN₃(20 mg, 0.31 mmol) was added to a solution of4-chloro-2-(methylthio)-6-(thiophen-2-yl)pyrimidine (33-01)(50 mg, 0.21mmol) in DMF in portions, and the reaction mixture was refluxed at 90°C. for 8 hrs. The reaction mixture was extracted by EtOAc/H₂O3 times.The organic layer was combined, washed with brine, dried over Na₂SO₄ andfurther purified by silica gel column chromatography (PE/EA=20/1) togive 21 mg of 4-azido-2-(methylthio)-6-(thiophen-2-yl)pyrimidine as awhite solid (41%).

mCPBA (36 mg, 0.21 mmol) was added to a solution of4-azido-2-(methylthio)-6-(thiophen-2-yl) pyrimidine (21 mg, 0.08 mmol)in DCM and the reaction mixture was stirred at room temperature for 2hrs. The reaction mixture was extracted by DCM and satured NaHCO₃solution 3 times. The organic layer was combined, washed with brine,dried over Na₂SO₄ and further purified by silica gel columnchromatography (PE/EA=1/1) to give 2 mg of4-azido-2-(methylsulfonyl)-6-(thiophen-2-yl) pyrimidine as a white solid(10%). ¹H NMR (400 Hz, CDCl₃) δ 7.94 (dd, J=1.2, 4.0 Hz, 1H), 7.90 (s,1H), 7.68 (dd, J=1.2, 4.8 Hz, 1H), 7.23 (dd, J=4.0, 4.8 Hz, 1H), 3.27(s, 3H). LC-MS (ESI) m/z: calcd for [C₉H₈N₅O₂S₂ ⁺], 282.0, found 282.2.

N,N-dimethyl-2-(methylsulfinyl)-6-(thiophen-2-yl)pyrimidin-4-amine (42)

To a solution of 4-chloro-2-(methylthio)-6-(thiophen-2-yl)pyrimidine(33-01) (50 mg, 0.21 mmol) in DMF (2 mL) was added dimethylamine (48 mg,1.04 mmol) dropwise. The reaction mixture was microwaved at 150° C. for30 min. the reaction mixture was cooled to room temperature, thenextracted by EtOAc and H₂O 3 times. The organic layer was combined,washed with brine, dried over Na₂SO₄, and then further purified bysilica gel column chromatography (PE/EA=10/1) to give 64 mg ofN,N-dimethyl-2-(methylthio)-6-(thiophen-2-yl) pyrimidin-4-amine as alight yellow oil (100%).

mCPBA (46 mg, 0.27 mmol) was added to a solution ofN,N-dimethyl-2-(methylthio)-6-(thiophen-2-yl) pyrimidin-4-amine (60 mg,0.27 mmol) in DCM and the reaction mixture was stirred at roomtemperature for 2 hrs. The reaction mixture was extracted by DCM andsatured NaHCO₃ solution 3 times. The organic layer was combined, washedwith brine, dried over Na₂SO₄ and further purified by silica gel columnchromatography (PE/EA=1/1) to give 25 mg ofN,N-dimethyl-2-(methylsulfinyl)-6-(thiophen-2-yl) pyrimidin-4-amine as awhite solid (40%). ¹H NMR (400 Hz, CDCl3) δ 7.76 (dd, J=1.2, 4.0 Hz,1H), 7.46 (dd, 1.2, 5.2 Hz, 1H), 7.12 (dd, J=4.0, 5.2 Hz, 1H), 6.62 (s,1H), 3.23 (s, 6H), 2.94 (s, 3H). LC-MS (ESI) m/z: calcd for [C₁₁H₁₄N₃OS₂⁺], 278.0, found 268.1.

4-(2-fluorophenyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (43)

Step 1. Preparation of 2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-ol(43-01)

To a solution of ethyl 4,4,4-trifluoro-3-oxobutanoate (2 g, 10.9 mmol)and methyl carbamimidothioate (4 g, 21.3 mmol) in EtOH (10 mL) was added10N NaOH solution (2 mL) dropwise under N₂ atmosphere. The reactionmixture was microwaved at 90° C. for 2 hrs. The reaction mixture wascooled to room temperature, then solvents were evaporated in vacuo. Theresidue was dissolved in H₂O and acidified to PH=2.0 with 1N HCl, thenextracted by DCM 3 times. The organic layer was combined, washed withbrine, dried over Na₂SO₄ and further purified by recrystallization withDCM/PE to give 1.8 g of 2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-olas a white solid (43-01)(8.5 mmol, 78%). ¹H NMR (400 MHz, DMSO): δ 6.59(s, 1H), 2.51 (s, 3H).

Step 2. Preparation of 2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yltrifluoromethanesulfonate (43-02)

To a solution of 2-mercapto-6-(trifluoromethyl)pyrimidin-4-ol (100 mg,0.48 mmol) and DIEA (184 mg, 1.4 mmol) in DCM (2 ml) was added drop wisetrifluoromethane sulfonic anhydride and (201 mg, 0.71 mmol) at 0° C. andstirred at RT over night. The mixture was extracted with H₂O/DCM (50mL/50 ml) 3 times, washed with brine (50 ml×3) and dried with Na₂SO₄,and then concentrated in vacuo and purified by chromatography(PE/EA=10/1) to give 90 mg the desired product as a light yellow oil,2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yltrifluoromethanesulfonate (0.26 mmol, y=55%)

Step 3. Preparation of4-(2-fluorophenyl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine (43-03)

To a solution of 2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yltrifluoromethanesulfonate (50 mg, 0.146 mmol) and 2-fluorophenylboronicacid (18 mg, 0.146 mmol) in dioxane (2 mL) was added PdCl₂(dppf) (10 mg,0.01 mmol) followed by Na₂CO₃ (2N, 1 mL) under N₂ atmosphere. Thereaction mixture was refluxed at 90° C. for 5 hrs. The reaction mixturewas cooled to room temperature and filtered over celite. Solvents wereremoved from the filtrate in vacuo, and the residue was extracted byDCM/H₂O (20 mL/20 mL) 3 times. The organic layer was combined, washedwith brine, dried over Na₂SO₄ and further purified by silica gel columnchromatography (PE/EA)=30/1 to give 30 mg of4-(2-fluorophenyl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine as alight yellow solid (0.11 mmol, 76%).

Step 4. Preparation of4-(2-fluorophenyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (43)

mCPBA (48 mg, 0.28 mmol) was added to a solution of4-(2-fluorophenyl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine (30 mg,0.11 mmol) in DCM and the reaction mixture was stirred at roomtemperature for 2 hrs. The reaction mixture was extracted by DCM andsatured NaHCO₃ solution 3 times. The organic layer was combined, washedwith brine, dried over Na₂SO₄ and further purified by silica gel columnchromatography (PE/EA=1/1) to give 12 mg of42-(methylsulfonyl)-4-phenyl-6-(trifluoromethyl) pyrimidine as a lightyellow solid (0.04 mmol, 35.8%). ¹H NMR (400 MHz, CDCl₃): δ 8.36-8.43(m, 1H), 8.3 (s, 1H), 7.60-7.66 (m, 1H), 7.37-7.42 (m, 1H), 7.25-7.31(m, 1H), 3.48 (s, 3H). LC-MS (ESI) m/z: calcd for [C₁₂H₉F₄N₂O₂S⁺],321.0, found 321.4.

4-(3-fluorophenyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (44)

The titled compound 44 (7 mg, 0.02 mmol) was prepared in a yield of 15%as a light yellow solid from 43-02 (50 mg, 0.146 mmol) and3-fluorophenylboronic acid (20 mg, 0.146 mmol) according to theprocedure for 60. ¹H NMR (400 MHz, CDCl₃): 8.18 (s, 1H), 8.01-8.04 (m,1H), 7.96-8.00 (m, 1H), 7.55-7.61 (m, 1H), 7.33-7.39 (m, 1H), 3.48 (s,3H). LC-MS (ESI) m/z: calcd for [C₁₂H₉F₄N₂O₂S⁺], 321.0, found 321.4.

4-(4-fluorophenyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (45)

The titled compound 45 (7 mg, 0.02 mmol) was prepared in a yield of 15%as a light yellow solid from 43-02 (50 mg, 0.146 mmol) and3-fluorophenylboronic acid (20 mg, 0.146 mmol) according to theprocedure for 60. LC-MS (ESI) m/z: calcd for [C₁₂H₉F₄N₂O₂S⁺], 321.0,found 321.4.

2-(methylsulfonyl)-4-(o-tolyl)-6-(trifluoromethyl)pyrimidine (46)

The titled compound 46 (2 mg, 0.006 mmol) was prepared in a yield of 4%as a light yellow solid from 43-02 (50 mg, 0.146 mmol) ando-tolylboronic acid (20 mg, 0.146 mmol) according to the procedure for43. ¹H NMR (400 MHz, CDCl3-d₆): δ 7.86 (s, 1H), 7.58-7.61 (m, 1H),7.46-7.61 (m, 1H), 7.37-7.41 (m, 2HH), 3.46 (s, 3H), 2.56 (s, 3H). LC-MS(ESI) m/z: calcd for [C₁₃H₁₂F₃N₂O₂S⁺], 317.0, found 317.4.

2-(methylsulfonyl)-4-(m-tolyl)-6-(trifluoromethyl)pyrimidine (47)

The titled compound 47 (2 mg, 0.006 mmol) was prepared in a yield of 4%as a light yellow solid from 43-02 (50 mg, 0.146 mmol) andm-tolylboronic acid (20 mg, 0.146 mmol) according to the procedure for43. ¹H NMR (400 MHz, CDCl3-d₆): δ 8.18 (s, 1H), 8.06 (s, 1H), 8.00-8.03(m, 1H), 7.46-7.68 (m, 2H), 3.48 (s, 3H), 2.49 (s, 3H). LC-MS (ESI) m/z:calcd for [C₁₃H₁₂F₃N₂O₂S⁺], 317.0, found 317.4.

2-(methylsulfonyl)-4-(p-tolyl)-6-(trifluoromethyl)pyrimidine (48)

The titled compound 48 (2 mg, 0.006 mmol) was prepared in a yield of 4%as a light yellow solid from 43-02 (50 mg, 0.146 mmol) andp-tolylboronic acid (20 mg, 0.146 mmol) according to the procedure for43. ¹H NMR (400 MHz, CDCl3-d₆): δ 8.15 (d, J=8.4 Hz, 1H), 8.14 (s, 1H),7.38 (d, J=8.4 Hz, 2H), 3.47 (s, 3H), 2.48 (s, 3H). LC-MS (ESI) m/z:calcd for [C₁₃H₁₂F₃N₂O₂S⁺], 317.0, found 317.4.

4-(4-ethynylphenyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine(49)

Step 1. Preparation of4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine (49-01)

A solution of 2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-ol(43-01)(1.4 g, 6.67 mmol) in POCl₃(15 mL) was refluxed at 120° C. for 3hrs. The reaction mixture was cooled to room temperature, and POCl₃ wasremoved in vacuo. The residue was extracted by DCM and icy H₂O 3 times.The organic layer was combined, washed with brine, dried over Na₂SO₄ andconcentrated to give 1.38 g of4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine as a light yellowoid (90%). LC-MS (ESI) m/z: calcd for [C₆H₅ClF₃N₂S⁺], 229.0, found229.0.

Step 2. preparation of4-(4-bromophenyl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine (49-02)

To a solution of 49-01(200 mg, 0.87 mmol) and (4-bromophenyl)boronicacid (195 mg, 0.97 mmol) in DME/H₂O (5 mL/1 mL) was added Pd(PPh₃)₄ (51mg, 0.04 mmol) followed by Na₂CO₃ (186 mg, 1.75 mmol) under N₂atmosphere. The reaction mixture was refluxed at 80° C. for 5 hrs. Thereaction mixture was cooled to room temperature and filtered overcelite. Solvents were removed in vacuo, and the residue was extracted byDCM and H₂O 3 times. The organic layer was combined, washed with brine,dried over Na₂SO₄ and further purified by silica gel columnchromatography (PE/EA)=50/1 to give 176 mg of4-(4-bromophenyl)-2-(methylthio)-6-(trifluoromethyl) pyrimidine (57%).¹H NMR (400 Hz, CDCl3) δ 8.00-8.03 (m, 2H), 7.66-7.68 (m, 2H), 7.62 (s,1H), 2.69 (s, 3H).

Step 3. Preparation of2-(methylthio)-4-(trifluoromethyl)-6-(4-((trimethylsilyl)ethynyl)phenyl)pyrimidine (49-03)

To a solution of 49-02 (176 mg, 0.50 mmol) in dry TEA was addedPd(PPh₃)₂Cl₂ (18 mg, 0.03 mmol), CuI (5 mg, 0.03 mmol) and P(t-Bu)₃(5mg, 0.03 mmol) under N₂ atmosphere. The reaction mixture was stirred for5 mins, followed by addition of ethynyltrimethylsilane(110 mg, 0.03mmol) dropwise. The reaction mixture was then refluxed at 80° C. for 4hrs. The reaction mixture was cooled to room temperature, filtered overcelite. Solvents were removed from the filtrate in vacuo, then theresidue was extracted by EtOAc/H₂O 3 times. The organic layer wascombined, washed with brine, dried over Na₂SO₄ and further purified bysilica gel column chromatography (PE/EA=4/1) to give 120 mg of2-(methylthio)-4-(trifluoromethyl)-6 (4-((trimethylsilyl) ethynyl)phenyl) pyrimidine as a white solid (65%). ¹H NMR (400 Hz, CDCl3) δ8.07-8.11 (m, 2H), 7.64 (s, 1H), 7.59-7.62 (m, 2H), 2.67 (s, 3H), 0.28(s, 9H).

Step 4. Preparation of4-(4-ethynylphenyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine

K₂CO₃(140 mg, 1.0 mmol) was added to a solution of 49-03 (120 mg, 0.33mmol) in MeOH dropwise. The reaction mixture was stirred at roomtemperature for 3 hrs. Solvents were removed in vacuo, and the residuewas extracted by EtOAc/H₂O 3 times. The organic layer was combined,washed with brine, dried over Na₂SO₄ and purified by silica gel columnchromatography (PE/EA=10/1) to give 35 mg of4-(4-ethynylphenyl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine as acolorless oil (36%).

An aqueous solution of Oxone (226 mg, 0.36 mmol) was added dropwise to asolution of4-(4-ethynylphenyl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine (15 mg,0.05 mmol) in MeOH (2 mL). The reaction mixture was stirred at roomtemperature for 8 hrs. Solvents were evaporated from the reactionmixture, then the residue was extracted by EtOAc/H₂O 3 times. Theorganic layer was combined, washed with brine, dried over Na₂SO₄ andfurther purified by silica gel column chromatography (PE/EA=10/1) togive 10 mg of4-(4-ethynylphenyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine asa light yellow solid (61%). ¹H NMR (400 Hz, CDCl3) δ 8.23 (d, J=8.4 Hz,2H), 8.19 (s, 1H), 7.69 (d, J=8.4 Hz, 2H), 3.48 (s, 1H), 3.33 (s, 1H).

3-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)phenol (50)

The titled compound 50 (3 mg, 0.006 mmol) was prepared in a yield of 8%as a white solid from 43-02 (21 mg, 0.058 mmol) and(3-hydroxyphenyl)boronic acid (16 mg, 0.058) according to the procedurefor 43. ¹H NMR (400 MHz, CDCl₃): δ 8.16 (s, 1H), 7.79 (t, J=2.0 Hz, 1H),7.74 (d, J=8.0 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.13 (dd, J=2.0, 8.0 Hz,1H), 3.48 (s, 3H). Mass (m/z): 319.4 [M+H]⁺.

4-(2-methoxyphenyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine(51)

The titled compound 51 (20 mg, 0.06 mmol) was prepared in a yield of 42%as a light yellow solid from 43-02 (50 mg, 0.146 mmol) and2-methoxyphenylboronic acid (22 mg, 0.146 mmol) according to theprocedure for 43. LC-MS (ESI) m/z: calcd for [C₁₃H₁₂F₃N₂O₃S₂ ⁺], 333.0,found 333.4.

4-(2-methoxyphenyl)-3-methylsulfonyl)-6-(trifluoromethyl)pyrimidine (52)

The titled compound (8 mg, 0.02 mmol) was prepared in a yield of 17% asa light yellow solid from 43-02 (50 mg, 0.146 mmol) and3-methoxyphenylboronic acid (22 mg, 0.146 mmol) according to theprocedure for 43. LC-MS (ESI) m/z: calcd for [C₁₃H₁₂F₃N₂O₃S₂ ⁺], 333.0,found 333.4.

4-(4-methoxyphenyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine(53) and4-(4-methoxyphenyl)-2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidine(54)

The titled compound 53 (11 mg, 0.03 mmol) was prepared in a yield of 23%as a light yellow solid from 43-02 (50 mg, 0.146 mmol) and4-methoxyphenylboronic acid (22 mg, 0.146 mmol) according to theprocedure for 43. LC-MS (ESI) m/z: calcd for [C₁₃H₁₂F₃N₂O₃S₂ ⁺], 333.0,found 333.4.

The titled compound 54 (11 mg, 0.03 mmol) was prepared in a yield of 23%as a light yellow solid from 43-02 (50 mg, 0.146 mmol) and4-methoxyphenylboronic acid (22 mg, 0.146 mmol) according to theprocedure for 43. LC-MS (ESI) m/z: calcd for [C₁₃H₁₂F₃N₂O₂S₂ ⁺], 317.0,found 317.4.

2-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)benzonitrile(55)

The titled compound 55 (14 mg, 0.04 mmol) was prepared in a yield of 29%as a light yellow solid from 43-02 (50 mg, 0.146 mmol) and2-cyanophenylboronic acid (21.4 mg, 0.146 mmol) according to theprocedure for 43. LC-MS (ESI) m/z: calcd for [C₁₃H₉F₃N₃O₂S₂ ⁺], 328.0,found 328.4.

3-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)benzonitrile(56)

The titled compound 56 (18 mg, 0.06 mmol) was prepared in a yield of 38%as a light yellow solid from 43-02 (50 mg, 0.146 mmol) and3-cyanophenylboronic acid (21.4 mg, 0.146 mmol) according to theprocedure for 43. ¹H NMR (400 MHz, CDCl3-d₆): δ 8.23 (s, 1H), 7.92-7.96(m, 1H), 7.78-7.81 (m, 1H), 7.60-7.62 (m, 2H), 3.50 (s, 3H). LC-MS (ESI)m/z: calcd for [C₁₃H₉F₃N₃O₂S₂ ⁺], 328.0, found 328.4.

4-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)benzonitrile (57)

The titled compound (18 mg, 0.06 mmol) was prepared in a yield of 40% asa light yellow solid from 43-02 (50 mg, 0.146 mmol) and4-cyanophenylboronic acid (21.4 mg, 0.146 mmol) according to theprocedure for 43. ¹H NMR (400 MHz, CDCl3-d₆): δ 8.36-8.39 (m, 2H), 8.24(s, 1H), 7.89-7.92 (m, 2H), 3.49 (s, 3H).

methyl 2-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)benzoate(58) and methyl2-(2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidin-4-yl)benzoate (59)

The titled compound 58 (13 mg, 0.04 mmol) was prepared in a yield of 25%as a light yellow solid from 43-02 (50 mg, 0.146 mmol) and2-(methoxycarbonyl)phenylboronic acid (26 mg, 0.146 mmol) according tothe procedure for 43. ¹H NMR (400 MHz, CDCl3-d₆): δ 7.96-8.00 (m, 1H),7.97 (s, 1H), 7.63-7.73 (m, 3H), 3.81 (s, 3H), 3.42 (s, 3H). LC-MS (ESI)m/z: calcd for [C₁₄H₁₂F₃N₂O₄S⁺], 361.0, found 361.4.

The titled compound 59 (3 mg, 0.01 mmol) was prepared in a yield of 7%as a light yellow solid from 43-02 (50 mg, 0.146 mmol) and2-(methoxycarbonyl)phenylboronic acid (26 mg, 0.146 mmol) according tothe procedure for 43. ¹H NMR (400 MHz, CDCl3-d₆): δ 7.96-7.99 (m, 1H),7.82 (s, 1H), 7.61-7.69 (m, 3H), 3.81 (s, 3H), 3.02 (s, 3H). LC-MS (ESI)m/z: calcd for [C₁₄H₁₂F₃N₂O₃S⁺], 345.0, found 345.4.

methyl 3-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)benzoate(60)

The titled compound 60 (14 mg, 0.04 mmol) was prepared in a yield of 26%as a light yellow solid from 43-02 (50 mg, 0.146 mmol) and3-methoxycarbonyl)phenylboronic acid (26 mg, 0.146 mmol) according tothe procedure for 43. ¹H NMR (400 MHz, CDCl3-d₆): δ 8.17 (s, 1H),7.76-7.79 (m, 2H), 7.50 (t, J=8.4 Hz, 1H), 7.18 (dd, J=3.4, 8.4 Hz, 1H),3.93 (s, 3H), 3.48 (s, 3H). LC-MS (ESI) m/z: calcd for [C₁₄H₁₂F₃N₂O₄S⁺],361.0, found 361.4.

methyl 4-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)benzoate(61) and methyl4-(2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidin-4-yl)benzoate (62)

The titled compound 61 (7 mg, 0.02 mmol) was prepared in a yield of 13%as a light yellow solid from 43-02 (50 mg, 0.146 mmol) and4-methoxycarbonyl)phenylboronic acid (26 mg, 0.146 mmol) according tothe procedure for 43. ¹H NMR (400 MHz, CDCl3-d₆): δ 8.31-8.34 (m, 2H),8.23-8.26 (m, 2H), 8.25 (s, 1H), 3.99 (s, 3H), 3.49 (s, 3H).

The titled compound 62 (7 mg, 0.02 mmol) was prepared in a yield of 17%as a light yellow solid from 43-02 (50 mg, 0.146 mmol) and4-methoxycarbonyl)phenylboronic acid (26 mg, 0.146 mmol) according tothe procedure for 43. LC-MS (ESI) m/z: calcd for [C₁₄H₁₂F₃N₂O₃S⁺],345.0, found 345.4.

2-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)benzoic acid(63)

methyl 2-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)benzoate (100mg, 0.305 mmol) in THF (8 mL) was added 4N NaOH (aq, 1 mL) dropwise. Thereaction mixture was then stirred at room temperature for 4 hrs.Solvents were evaporated in vacuo, and the residue was extracted byEtOAC and H₂O 3 times. The organic layer was combined, washed withbrine, dried over Na₂SO₄, concentrated and further purified by silicagel column chromatography to give 95 mg of2-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)benzoic acid as awhite solid.

mCPBA (10 mg, 0.04 mmol) was added to a solution of2-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)benzoic acid (10 mg,0.03 mmol) in DCM and the reaction mixture was stirred at roomtemperature for 2 hrs. The reaction mixture was extracted by DCM andsatured NaHCO₃ solution 3 times. The organic layer was combined, washedwith brine, dried over Na₂SO₄ and further purified by silica gel columnchromatography (PE/EA=1/1) to give 3 mg of2-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)benzoic acid asa light yellow solid (0.006 mmol, 27%). ¹H NMR (400 MHz, CDCl3-d₆): δ8.10 (d, J=8.0 Hz, 1H), 8.00 (s, 1H), 7.69-7.75 (m, 2H), 7.40 (d, J=8.0Hz, 1H), 3.42 (s, 3H). LC-M S (ESI) m % z: calcd for [C₁₃H₁₀F₃N₂O₄S⁺],347.0, found 347.4.

4-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)benzoic acid(64) and 4-(2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidin-4-yl)benzoicacid (65)

The titled compound 64 (5 mg, 0.01 mmol) was prepared in a yield of 32%as a light yellow solid from4-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)benzoic acid (10 mg,0.03 mmol) and according to the procedure for 63. LC-MS (ESI) m/z: calcdfor [C₁₃H₁₀F₃N₂O₄S⁺], 347.0, found 347.4.

The titled compound 65 (3 mg, 0.006 mmol) was prepared in a yield of 20%as a light yellow solid from4-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)benzoic acid (10 mg,0.03 mmol) and according to the procedure for 63. ¹H NMR (400 MHz,CDCl3-d₆): δ 8.29-8.33 (m, 2H), 8.19-8.23 (m, 2H), 8.11 (s, 1H), 3.13(s, 3H).

3-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)benzamide (66)

The titled compound (7 mg, 0.02 mmol) was prepared in a yield of 14% asa light yellow solid from 43-02 (50 mg, 0.146 mmol) and(3-((tert-butoxycarbonyl)carbamoyl)phenyl)boronic acid (40 mg, 0.146mmol) according to the procedure for 43. ¹H NMR (400 MHz, CDCl3-d₆): δ8.95 (s, 1H), 8.85 (s, 1H), 8.60 (d, J=8.0 Hz, 1H), 8.23 (s, 1H), 8.18(d, J=8.0 Hz, 1H), 7.75 (t, J=8.0 Hz, 1H0, 7.64 (s, 1H0, 3.58 (s, 3H).

N-methyl-2-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)benzamide(67)

To a solution of2-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)benzoic acid (10 mg,0.03 mmol) in DMF (1 mL) was added CH₃NH₂.HCl (1eq), DIPEA (2.5eq), HATU(1.2eq) and the reaction mixture was stirred at room temperatureovernight. Solvents were evaporated in vacuo, and the residue wasextracted by EtOAC and H₂O 3 times. The organic layer was combined,washed with brine, dried over Na₂SO₄, concentrated and further purifiedby silica gel column chromatography to give 10 mg ofN-methyl-2-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)benzamide(89%) as a white solid.

mCPBA (10 mg, 0.04 mmol) was added to a solution ofN-methyl-2-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)benzamide(10 mg, 0.03 mmol) in DCM and the reaction mixture was stirred at roomtemperature for 2 hrs. The reaction mixture was extracted by DCM andsatured NaHCO₃ solution 3 times. The organic layer was combined, washedwith brine, dried over Na₂SO₄ and further purified by silica gel columnchromatography (PE/EA=1/1) to give 8 mg of2-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)benzoic acid asa light yellow solid (0.02 mmol, 70%). LC-MS (ESI) m/z: calcd for[C₁₄H₁₃F₃N₃O₃S⁺], 360.1, found 360.4.

Synthesis ofN-methyl-4-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)benzamide(68)

The titled compound 68 (7 mg, 0.02 mmol) was prepared in a yield of 62%as a light yellow solid from4-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)benzoic acid (10 mg,0.03 mmol) and CH₃NH₂.HCl according to the procedure for 67. ¹H NMR (400MHz, CDCl3-d₆): δ 8.29 (d, J=8.8 Hz, 2H), 8.23 (s, 1H), 7.96 (d, J=8.8Hz, 2H), 3.48 (s, 3H), 3.06 (d, J=4.8 Hz, 3H). LC-MS (ESI) m/z: calcdfor [C₁₄H₁₃F₃N₃O₃S⁺], 360.1, found 360.4.

N,N-dimethyl-3-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)benzamide(69)

The titled compound 69 (2 mg, 0.004 mmol) was prepared in a yield of 8%as a light yellow solid from3-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)benzoic acid (20 mg,0.06 mmol) and dimethylamine according to the procedure for 67. ¹H NMR(400 MHz, DMSO): δ 8.97 (s, 1H), 8.49-8.53 (m, 1H), 8.46 (s, 1H),7.70-7.72 (m, 2H), 3.56 (s, 3H), 3.04 (s, 3H), 2.94 (s, 3H). LC-MS (ESI)m/z: calcd for [C₁₅H₁₅F₃N₃O₃S⁺], 374.0, found 374.5.

1-(3-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)benzyl)pyridin-2(1H)-one (70)

The titled compound 70 (12 mg, 0.03 mmol) was prepared in a yield of 21%as a light yellow solid from 43-02 (50 mg, 0.146 mmol) and1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyridin-2(1H)-one(45 mg, 0.146 mmol) according to the procedure for 43. ¹H NMR (400 Hz,DMSO) δ 8.86 (s, 1H), 8.41 (s, 1H), 8.37 (d, J=8.0 Hz, 1H), 7.89 (s,J=2.0, 6.8 Hz, 1H), 7.59-7.64 (m, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.42-7.48(m, 1H), 6.44 (d, J=9.2 Hz, 1H), 6.26-6.30 (m, 1H), 5.24 (s, 2H), 3.54(s, 3H). LC-MS (ESI) m/z: calcd for [C₁₈H₁₅F₃N₃O₃S⁺], 410.1, found410.5.

2-(methylsulfonyl)-4-(3-(prop-2-yn-1-yloxy)phenyl)-6-(trifluoromethyl)pyrimidine (71) and2-(methylsulfinyl)-4-(3-(prop-2-yn-1-yloxy)phenyl)-6-(trifluoromethyl)pyrimidine (72)

Step 1. Preparation of3-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)phenol (71-01)

To a solution of 4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine(200 mg, 0.87 mmol) and (3-hydroxyphenyl)boronic acid (150 mg, 1.05mmol) in DME/H₂O (5 mL/1 mL) was added Pd(dppf)₂Cl₂ (32 mg, 0.04 mmol)followed by Na₂CO₃ (280 mg, 2.62 mmol) under N₂ atmosphere. The reactionmixture was refluxed at 110° C. for 5 hrs. The reaction mixture wascooled to room temperature and filtered over celite. Solvents wereremoved in vacuo, and the residue was extracted by DCM and H₂O 3 times.The organic layer was combined, washed with brine, dried over Na₂SO₄ andfurther purified by silica gel column chromatography (PE/EA=30/1) togive 104 mg of3-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)phenol (71-01) as awhite solid (41%).

Step 2. Preparation of2-(methylsulfonyl)-4-(3-(prop-2-yn-1-yloxy)phenyl)-6-(trifluoromethyl)pyrimidine (89) and2-(methylsulfinyl)-4-(3-(prop-2-yn-1-yloxy)phenyl)-6-(trifluoromethyl)pyrimidine (90)

K₂CO₃(76 mg, 0.54 mmol) was added to a solution of 71-01 (104 mg, 0.36mmol) and 3-bromoprop-1-yne (52 mg, 0.44 mmol) in DMF (2 mL). Thereaction mixture was stirred at room temperature for 3 hrs. The reactionmixture was extracted by EtOAc and H₂O 3 times. The organic layer wascombined, washed with brine, dried over Na₂SO₄, concentrated and furtherpurified by silica gel column chromatography (PE/EA=4/1), to give 105 mgof2-(methylthio)-4-(3-(prop-2-yn-1-yloxy)phenyl)-6-(trifluoromethyl)pyrimidineas a white solid (90%). An aqueous solution of Oxone (1 g, 1.51 mmol)was added dropwise to a solution of2-(methylthio)-4-(3-(prop-2-yn-1-yloxy)phenyl)-6-(trifluoromethyl)pyrimidine(70 mg, 0.22 mmol) in MeOH. The reaction mixture was stirred at roomtemperature for 8 hrs. Solvents were evaporated from the reactionmixture, then the residue was extracted by EtOAc/H₂O 3 times. Theorganic layer was combined, washed with brine, dried over Na₂SO₄ andfurther purified by silica gel column chromatography (PE/EA=6/1) to give22 mg of2-(methylsulfonyl)-4-(3-(prop-2-yn-1-yloxy)phenyl)-6-(trifluoromethyl)pyrimidine(71) as a colorless oil and 6 mg of2-(methylsulfinyl)-4-(3-(prop-2-yn-1-yloxy)phenyl)-6-(trifluoromethyl)pyrimidine as a colorless oil (72). ¹H NMR for 71 (400 Hz, CDCl3) δ 8.04(s, 1H), 7.86-7.83 (m, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.24 (dd, J=2.0, 8.0Hz, 1H), 4.81 (d, J=2.4 Hz, 2H), 3.07 (s, 3H), 2.57 (t, J=2.4 Hz, 1H).LC-MS (ESI) m/z: calcd for [C₁₅H₁₂F₃N₂O₂S⁺], 341.1, found 341.0.

¹H NMR for 72 (400 Hz, CDCl₃) δ 8.16 (s, 1H), 7.85-7.80 (m, 2H), 7.51(t, J=8.0 Hz, 1H), 7.25 (dd, J=2.0, 8.0 Hz, 1H), 4.80 (d, J=2.4 Hz, 2H),3.47 (s, 3H), 2.57 (t, J=2.4 Hz, 1H). LC-MS (ESI) m/z: calcd for[C₁₅H₁₂F₃N₂O₃S⁺], 357.1, found 357.0.

2-(methylsulfonyl)-4-(3-phenoxyphenyl)-6-(trifluoromethyl)pyrimidine(73) and2-(methylsulfinyl)-4-(3-phenoxyphenyl)-6-(trifluoromethyl)pyrimidine(74)

Step 1. Preparation of2-(methylthio)-4-(3-phenoxyphenyl)-6-(trifluoromethyl)pyrimidine

A solution of 4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine (30mg, 0.13 mmol), (3-phenoxyphenyl)boronic acid (41 mg, 0.14 mmol),Pd(PPh₃)₄ (8 mg, 0.007 mmol) and 1 M Na₂CO₃ aqueous solution (0.39 mL,0.39 mmol) in DME (2 mL) under nitrogen was heated 100° C. for 5 h. Themixture was cooled to RT and extracted with DCM (30 mL). The organiclayer was separated, dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by Pre-TLC (EtOAc/PE=1:30) to obtain theproduct as a white solid (10 mg, 21%). Mass (m/z): 363.4 [M+H]⁺.

Step 2. Preparation of2-(methylsulfonyl)-4-(3-phenoxyphenyl)-6-(trifluoromethyl)pyrimidine(73) and2-(methylsulfinyl)-4-(3-phenoxyphenyl)-6-(trifluoromethyl)pyrimidine(74)

To a solution of2-(methylthio)-4-(3-phenoxyphenyl)-6-(trifluoromethyl)pyrimidine (10 mg,0.03 mmol) in MeOH (2 mL) was added oxone (51 mg, 0.09 mmol) in H₂O (2mL). Then the mixture was stirred at RT for 3 h. The solvent was removedand extracted with DCM (20 mL). The organic layer was separated, driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby Pre-TLC (EtOAc/PE=1:2) to obtain 73 as a white solid (3 mg) and 74 asa white solid (4 mg). For 73, ¹H NMR: (400 Mz, CDCl3): δ 8.13 (s, 1H),7.95 (dd, J=0.8, 7.6 Hz, 1H), 7.87 (s, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.39(t, J=8.0 Hz, 2H), 7.18 (dt, J=0.8, 7.6 Hz, 2H), 7.06 (d, J=8.0 Hz, 2H),3.44 (s, 3H). Mass (m/z): 395.3 [M+H]⁺. For 74, ¹H NMR: (400 Mz, CDCl3):δ 8.01 (s, 1H), 7.97 (dd, J=0.8, 7.6 Hz, 1H), 7.88 (s, 1H), 7.52 (t,J=8.0 Hz, 1H), 7.38 (t, J=8.0 Hz, 2H), 7.18 (dt, J=0.8, 7.6 Hz, 2H),7.06 (d, J=8.0 Hz, 2H), 3.05 (s, 3H). Mass (m/z): 379.4 [M+H]⁺.

4-(3-(benzyloxy)phenyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine(75)

Step 1. Preparation of4-(3-(Benzyloxy)phenyl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine

Cs₂CO₃ (68 mg, 0.20 mmol) was added to a solution of3-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)phenol (30 mg, 0.10mmol) in anhydrous CH₃CN (5 mL) at 0° C. After stirring for 30 min,benzyl bromide (27 mg, 0.15 mmol) was added dropwise and stirred at RTfor 3 h. After evaporation the organic solvents, the residue waspurified by column chromatography (200-300 mesh silica gel, eluted withEtOAc/PE=1:25) to give the product as a white solid (10 mg, 26%). Mass(m/z): 377.4 [M+H]⁺.

Step 2. Preparation of4-(3-(benzyloxy)phenyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine(93)

To a solution of4-(3-(Benzyloxy)phenyl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine (10mg, 0.03 mmol) in DCM (2 mL) was added m-CPBA (14 mg, 0.09 mmol) at RT.Then the mixture was stirred at RT for 3 h. The solvent was removed andextracted with DCM (20 mL). The organic layer was separated, dried overNa₂SO₄, filtered and concentrated. The crude product was purified byPre-TLC (EtOAc/PE=1:2) to obtain 75 as a white solid (3 mg, 24%): ¹H NMR(400 MHz, CDCl₃) of: δ 8.15 (s, 1H), 7.86 (s, 1H), 7.79 (d, J=8.0 Hz,1H), 7.51-7.34 (m, 7H), 5.18 (s, 2H), 3.46 (s, 3H). Mass (m/z): 409.4[M+H]⁺.

2-(methylsulfonyl)-4-(naphthalen-1-yl)-6-(trifluoromethyl)pyrimidine(76) and2-(methylsulfinyl)-4-(naphthalen-1-yl)-6-(trifluoromethyl)pyrimidine(77)

The titled compound 76 (2 mg, 0.003 mmol) was prepared in a yield of 2%as a light yellow solid from 43-02 (50 mg, 0.146 mmol) andnaphthalen-1-ylboronic acid (25 mg, 0.146 mmol) according to theprocedure for 43. ¹H NMR (400 MHz, CDCl3-d₆): δ 8.21-8.24 (m, 1H), 8.17(s, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.95-8.00 (m, 1H), 7.83 (dd, J=1.2, 7.2Hz, 1H), 7.58-7.66 (m, 3H), 3.48 (s, 3H). LC-MS (ESI) m/z: calcd for[C₁₆H₁₂F₃N₂O₂S⁺], 353.1, found 337.4.

The titled compound 77 (8 mg, 0.012 mmol) was prepared in a yield of 7%as a light yellow solid from 43-02 (50 mg, 0.146 mmol) andnaphthalen-1-ylboronic acid (25 mg, 0.146 mmol) according to theprocedure for 43. LC-MS (ESI) m/z: calcd for [C₁₆H₁₂F₃N₂OS⁺], 337.0,found 337.4.

4-(2-Methoxypyridin-3-yl)-2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidine(78)

Step 1. Preparation of4-(2-Methoxypyridin-3-yl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine(78-01)

To a solution of 2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yltrifluoromethanesulfonate (112 mg, 0.33 mmol),(2-methoxypyridin-3-yl)boronic acid (50 mg, 0.33 mmol), Pd(dppf)Cl₂ (12mg, 0.02 mmol) and 2 M Na₂CO₃ aqueous solution (0.49 mL, 0.99 mmol) inDME (10 mL) under nitrogen was heated 100° C. for 4 h. The mixture wascooled to RT and extracted with DCM (3×20 mL). The organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by column chromatography (200-300 mesh silica gel,eluted with EtOAc/PE=1:40) to obtain the product as a white solid (10mg, 10%): ¹H NMR (400 MHz, CDCl₃): δ 8.57 (dd, J=2.0, 7.6 Hz, 1H), 8.32(dd, J=2.0, 4.8 Hz, 1H), 8.11 (s, 1H), 7.08 (dd, J=4.8, 7.6 Hz, 1H),4.10 (s, 3H), 2.65 (s, 3H). Mass (m/z): 302.3 [M+H]⁺.

Step 2. Preparation of4-(2-Methoxypyridin-3-yl)-2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidine(79) and4-(2-methoxypyridin-3-yl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine(78)

To a solution of4-(2-methoxypyridin-3-yl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine(10 mg, 0.03 mmol) in DCM (2 mL) was added m-CPBA (16 mg, 0.09 mmol) atRT. Then the mixture was stirred at RT for 3 h. The solvent was removedand extracted with DCM (20 mL). The organic layer was separated, driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby Pre-TLC (EtOAc/PE=1:2) to obtain 79 as a white solid (3 mg) and 78 asa white solid (4 mg). For 79, ¹H NMR (400 MHz, CDCl₃) of: θ 8.81 (dd,J=2.0, 7.6 Hz, 1H), 8.60 (s, 1H), 8.39 (dd, J=2.0, 4.8 Hz, 1H), 7.13 (d,J=4.8, 7.6 Hz, 1H), 4.15 (s, 3H), 3.05 (s, 3H). Mass (m/z): 318.4[M+H]⁺. For 78, ¹H NMR (400 MHz, CDCl₃) of: δ 8.78 (dd, J=2.0, 7.6 Hz,1H), 8.73 (s, 1H), 8.41 (dd, J=2.0, 4.8 Hz, 1H), 7.15 (dd, J=4.8, 7.6Hz, 1H), 4.16 (s, 3H), 3.46 (s, 3H). Mass (m/z): 334.3 [M+H]⁺.

3-(2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(81) and3-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(80)

Step 1. Preparation of3-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl) pyridine-2(1H)-one(80-01)

A solution of4-(2-methoxypyridin-3-yl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine(50 mg, 0.17 mmol) in 10/3 (v:v) of HBr/EtOH (2.5 mL) was heated to 100°C. for 2 h. Then the solvents were removed and adjusted pH to 7 withsaturated aqueous NaHCO₃ solution. Then the solid was precipitate outand filtered to give product as a white solid (42 mg, 94%). ¹H NMR (400MHz, DMSO-d₆): δ 12.46 (br, 1H), 8.85 (s, 1H), 8.78 (dd, J=2.4, 7.2 Hz,1H), 7.79 (dd, J=2.4, 6.4 Hz, 1H), 6.52 (dd, J=6.4, 7.2 Hz, 1H), 2.63(s, 3H). Mass (m/z): 288.03 [M+H]⁺.

Step 2.3-(2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(81) and3-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(80)

To a solution of3-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(10 mg, 0.03 mmol) in MeOH (1 mL) was added oxone (64 mg, 0.09 mmol) inH₂O (1 mL). Then the mixture was stirred at RT for 3 h. The solvent wasremoved and extracted with DCM (20 mL). The organic layer was separated,dried over Na₂SO₄, filtered and concentrated. The crude product waspurified by Pre-TLC (EtOAc/PE=3:2) to obtain 81 as a white solid (3 mg)and 80 as a white solid (3 mg). For 81, ¹H NMR: (400 Mz, CD₃OD): δ 9.29(s, 1H), 9.08 (dd, J=1.6, 7.2 Hz, 1H), 7.78 (dd, J=1.6, 6.4 Hz, 1H),6.64 (dd, J=6.4, 7.2 Hz, 1H), 3.06 (s, 3H). Mass (m/z): 304.2 [M+H]⁺.For 80, ¹H NMR: (400 Mz, CD₃OD): δ 9.42 (s, 1H), 9.03 (dd, J=1.6, 7.2Hz, 1H), 7.81 (dd, J=1.6, 6.4 Hz, 1H), 6.66 (dd, J=6.4, 7.2 Hz, 1H),3.48 (s, 3H). Mass (m/z): 320.3 [M+H]⁺.

4-(2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidin-4-yl)morpholine (82)

The titled compound 82 was prepared in a yield of 55% (5 mg, 0.02 mmol)as a white solid from 43-02 (50 mg, 0.146 mmol) and morpholine (13 mg,0.15 mmol) according to the procedure for 36. ¹H NMR (400 MHz,CDCl3-d₆): δ 6.78 (s, 1H), 3.80-3.83 (m, 4H), 2.93 (s, 3H).

2-(methylsulfonyl)-4-(1H-pyrazol-1-yl)-6-(trifluoromethyl)pyrimidine(83)

The titled compound (10 mg, 0.02 mmol) was prepared in a yield of 10% asa light yellow solid from 43-02 (50 mg, 0.146 mmol) and 1H-pyrazole (10mg, 0.146 mmol) according to the procedure for 36. ¹H NMR (400 MHz,CDCl3-d₆): δ 8.70 (dd, J=0.8, 2.0 Hz, 1H), 8.43 (s, 1H), 7.91 (m, 1H),6.63 (dd, J=1.6, 2.4 Hz, 1H), 3.45 (s, 3H).

2-(methylsulfonyl)-4-(1H-pyrrol-2-yl)-6-(trifluoromethyl)pyrimidine (84)

Step 1. Preparation of2-(methylthio)-4-(1H-pyrrol-2-yl)-6-(trifluoromethyl)pyrimidine (84-01)

To a solution of 4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine(94.9 mg, 0.42 mmol), 1-(tert-butoxycarbonyl)-1H-pyrrol-2-ylboronic acid(87 mg, 0.42 mmol), Pd(pph₃)₄ (24.1 mg, 0.02 mmol) and Na₂CO₃(1 ml) inDME (3 ml) under nitrogen was heated 105° C. for 3 h. The mixture wascooled to RT and extracted with DCM (3*20 mL). The organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by Prep.TLC to obtain the product (60 mg) as awhite solid. Mass (m/z): 260.04 [M+H]⁺.

Step 2. Preparation of2-(methylsulfonyl)-4-(1H-pyrrol-2-yl)-6-(trifluoromethyl)-pyrimidine

To a solution of2-(methylthio)-4-(1H-pyrrol-2-yl)-6-(trifluoromethyl)pyrimidine (10 mg,0.038 mmol) in MeOH (2 ml) was added oxone (108 mg, 0.17 mmol) in H₂O (2ml). Then the mixture was stirred at RT for 5 h. The solvent was removedand extracted with DCM (3*15 ml). The organic layer was separated, driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby Prep.TLC to obtain the product (5.1 mg, 45.1%) as a white solid.¹H-NMR (400 MHz, CDCl₃): δ 10.17 (s, 1H), 7.74 (s, 1H), 7.17-7.16 (m,2H), 6.44-6.42 (m, 1H), 3.40 (s, 3H). Mass (m/z): 292.03 [M+H]⁺.

4-(1-(3,4-dimethoxybenzyl)-1H-pyrrol-2-yl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine(85) and4-(1-(3,4-dimethoxybenzyl)-1H-pyrrol-2-yl)-2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidine(86)

Step 1. Preparation of4-(1-(3,4-dimethoxybenzyl)-1H-pyrrol-2-yl)-2-(methylthio)-6-(tri-fluoromethyl)pyrimidine(85-01)

To a solution of2-(methylthio)-4-(1H-pyrrol-2-yl)-6-(trifluoromethyl)pyrimidine (40.0mg, 0.15 mmol) and NaH (14.0 mg, 0.28 mmol) in anhydrous DMF (3 ml) wasstirred at 0° C. for 15 min. Then to the mixture was added4-(bromomethyl)-1,2-dimethoxybenzene (42.6 mg, 0.18 mmol) and stirred atRT for 4 h. Then the reaction mixture was poured into water andextracted with EA (3*15 mL) and the organic layer was separated, driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby Prep.TLC to obtain the product (43.0 mg) as a white solid. Mass(m/z): 410.11[M+H]⁺.

Step 2. Preparation of4-(1-(3,4-dimethoxybenzyl)-1H-pyrrol-2-yl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine(85) and4-(1-(3,4-dimethoxybenzyl)-1H-pyrrol-2-yl)-2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidine(86)

To a solution of4-(1-(3,4-dimethoxybenzyl)-1H-pyrrol-2-yl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine(40 mg, 0.097 mmol) in MeOH (3 ml) was added oxone (293.4 mg, 0.47 mmol)in H₂O (3 ml). Then the mixture was stirred at RT for 4 h. The solventwas removed and extracted with DCM (3*15 ml). The organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by Prep.TLC to obtain the 85 (15 mg, 23.25%) as awhite solid. And 86 5.0 mg (12.07%) as a white solid

85 ¹H-NMR (400 Mz, CDCl₃): δ 7.76 (s, 1H), 7.18-7.15 (m, 2H), 6.82 (d,J=2.0 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 6.57 (dd, J=2.0 Hz, ²J=8 Hz, 1H),6.39-6.37 (m, 1H), 5.79 (s, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 3.45 (s,3H). Mass (m/z): 442.10[M+H]⁺.

86 ¹H-NMR (400 Mz, CDCl₃): δ 7.72 (s, 1H), 7.08-7.07 (m, 2H), 6.85 (d,J=2.4 Hz, 1H), 6.76 (d, J=7.2 Hz, 1H), 6.63 (dd, ¹J=2.4 Hz, ²J=7.2 Hz,1H), 6.63-6.61 (m, 1H), 5.74 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.28(s, 3H). Mass (m/z): 426.10[M+H]⁺.

2-(methylsulfonyl)-4-(1H-pyrrol-3-yl)-6-(trifluoromethyl)pyrimidine (87)and 2-(methylsulfinyl)-4-(1H-pyrrol-3-yl)-6-(trifluoromethyl)pyrimidine(88)

Step 1. Preparation of2-(methylthio)-4-(1H-pyrrol-3-yl)-6-(trifluoromethyl)pyrimidine (87-01)

To a solution of 4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine(228 mg, 1 mmol), (1-(triisopropylsilyl)-1H-pyrrol-3-yl)boronic acid(267 mg, 1 mmol), Pd(PPh₃)₄(58 mg, 0.05 mmol) and 1 M Na₂CO₃ aqueoussolution (3 mL, 3 mmol) in DME (10 mL) under nitrogen was heated 100° C.for 5 h. The mixture was cooled to RT and extracted with DCM (3×30 mL).The organic layer was separated, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by column chromatography(200˜300 mesh silica gel, eluted with EtOAc/PE=1:50-1:10) to obtain theproduct as a white solid (190 mg, 73%). Mass (m/z): 260.2 [M+H]⁺.

Step 2.2-(methylsulfonyl)-4-(1H-pyrrol-3-yl)-6-(trifluoromethyl)pyrimidine (87)and 2-(methylsulfinyl)-4-(1H-pyrrol-3-yl)-6-(trifluoromethyl)pyrimidine(88)

To a solution of2-(methylthio)-4-(1H-pyrrol-3-yl)-6-(trifluoromethyl)pyrimidine (50 mg,0.2 mmol) in MeOH (3 mL) was added oxone (356 mg, 0.6 mmol) in H₂O (3mL). Then the mixture was stirred at RT for 3 h. The solvent was removedand extracted with DCM (50 mL). The organic layer was separated, driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby Pre-TLC (EtOAc/PE=1:2) to obtain 87 as a white solid (12 mg, 13%) and88 as a white solid (15 mg, 17%). For 87, ¹H NMR: (400 Mz, CDCl3): δ8.80-8.75 (m, 1H), 7.86-7.82 (m, 1H), 7.75 (s, 1H), 6.94-6.91 (m, 1H),6.86-6.82 (m, 1H), 3.42 (s, 3H). Mass (m/z): 292.2 [M+H]⁺. For 88, ¹HNMR: (400 Mz, CDCl3): δ 9.39-9.36 (m, 1H), 7.86-7.84 (m, 1H), 7.64 (s,1H), 6.92-6.90 (m, 1H), 6.81-6.78 (m, 1H), 3.02 (s, 3H). Mass (m/z):276.3 [M+H]⁺.

4-(1-(3-methoxybenzyl)-1H-pyrrol-3-yl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine(89) and4-(1-(3-methoxybenzyl)-1H-pyrrol-3-yl)-2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidine(90)

Step 1. Preparation of4-(1-(3-methoxybenzyl)-1H-pyrrol-3-yl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine

To a solution of2-(methylthio)-4-(1H-pyrrol-3-yl)-6-(trifluoromethyl)pyrimidine (30 mg,0.11 mmol) in anhydrous DMF (2 mL) was added NaH (5 mg, 0.12 mmol) at 0°C. and stirred for 30 min. Then to the mixture was added1-(bromomethyl)-3-methoxybenzene (24 mg, 0.12 mmol) and stirred at RTfor 5 h. Then the reaction mixture was poured into water and extractedwith EA (2×15 mL) and the organic layer was separated, dried overNa₂SO₄, filtered and concentrated. The crude product was purified byPre-TLC (EtOAc/PE=1:7) to give the product (36 mg, 82%) as a whitesolid. Mass (m/z): 380.4 [M+H]⁺.

Step 2. Preparation of4-(1-(3-methoxybenzyl)-1H-pyrrol-3-yl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (89) and4-(1-(3-methoxybenzyl)-1H-pyrrol-3-yl)-2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidine(90)

To a solution of4-(1-(3-methoxybenzyl)-1H-pyrrol-3-yl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine(40 mg, 0.11 mmol) in MeOH (1.5 mL) was added oxone (203 mg, 0.33 mmol)in H₂O (1.5 mL). Then the mixture was stirred at RT for 3 h. The solventwas removed and extracted with DCM (20 mL). The organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by Pre-TLC (EtOAc/PE=3:2) to obtain 89 as a whitesolid (14 mg, 31%) and 90 as a white solid (11 mg, 24%). For 89, ¹H NMR:(400 Mz, CDCl₃): δ 7.74 (s, 1H), 7.68 (s, 1H), 7.28 (t, J=8.0 Hz, 1H),6.86 (dd, J=2.4, 8.4 Hz, 1H), 6.79-6.75 (m, 3H), 6.68 (s, 1H), 5.08 (s,2H), 3.78 (s, 3H), 3.39 (s, 3H). Mass (m/z): 412.2 [M+H]⁺. For 90, ¹HNMR: (400 Mz, CDCl₃): δ 7.75 (s, 1H), 7.59 (s, 1H), 7.28 (t, J=8.0 Hz,1H), 6.87 (dd, J=2.4, 8.4 Hz, 1H), 6.78-6.75 (m, 3H), 6.69 (s, 1H), 5.08(s, 2H), 3.78 (s, 3H), 2.99 (s, 3H). Mass (m/z): 396.4 [M+H]⁺.

4-(1-(4-methoxybenzyl)-1H-pyrrol-3-yl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine(91) and4-(1-(4-methoxybenzyl)-1H-pyrrol-3-yl)-2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidine(92)

The titled compound 91 (5 mg, 11% yield) and 92 (5 mg, 11% yield) wasprepared as two white solids from 87-01 (30 mg, 0.11 mmol) and1-(bromomethyl)-4-methoxybenzene (24 mg, 0.12 mmol) according to theprocedure for 89.

91 ¹H NMR: (400 Mz, CDCl₃): δ 7.74-7.71 (m, 1H), 7.67 (s, 1H), 7.16-7.12(m, 2H), 6.91-6.85 (m, 2H), 6.77-6.74 (m, 2H), 5.04 (s, 2H), 3.81 (s,3H), 3.39 (s, 3H). Mass (m/z): 412.3 [M+H]⁺.

92 ¹H NMR: (400 Mz, CDCl₃): δ 7.74-7.72 (m, 1H), 7.57 (s, 1H), 7.16-7.13(m, 2H), 6.91-6.88 (m, 2H), 6.76-6.74 (m, 2H), 5.04 (s, 2H), 3.80 (s,3H), 2.98 (s, 3H). Mass (m/z): 396.4 [M+H]⁺.

4-(1-(3-chlorobenzyl)-1H-pyrrol-3-yl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine(93) and4-(1-(3-chlorobenzyl)-1H-pyrrol-3-yl)-2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidine(94)

The titled compound 93 (5 mg, 11% yield) and 94 (5 mg, 11% yield) wasprepared as two white solids from 87-01 (30 mg, 0.11 mmol) and1-(bromomethyl)-3-chlorobenzene (24 mg, 0.12 mmol) according to theprocedure for 89.

93 ¹H NMR: (400 Mz, CDCl₃): δ 7.74-7.73 (m, 1H), 7.70 (s, 1H), 7.32-7.29(m, 2H), 7.14 (s, 1H), 7.06-7.04 (m, 1H), 6.80-6.76 (m, 2H), 5.09 (s,2H), 3.40 (s, 3H). Mass (m/z): 416.4 [M+H]⁺.

94 ¹H NMR: (400 Mz, CDCl₃): δ 7.77-7.73 (m, 1H), 7.60 (s, 1H), 7.31-7.29(m, 2H), 7.14 (s, 1H), 7.06-7.04 (m, 1H), 6.80-6.74 (m, 2H), 5.09 (s,2H), 2.99 (s, 3H). Mass (m/z): 340.6 [M+H]⁺.

4-(1-(4-chlorobenzyl)-1H-pyrrol-3-yl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine(95) and4-(1-(4-chlorobenzyl)-1H-pyrrol-3-yl)-2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidine(96)

The titled compound 95 (5 mg, 11% yield) and 96 (5 mg, 11% yield) wasprepared as two white solids from 87-01 (30 mg, 0.11 mmol) and1-(bromomethyl)-4-chlorobenzene (24 mg, 0.12 mmol) according to theprocedure for 89.

95 ¹H NMR: (400 Mz, CDCl₃): δ 7.75-7.73 (m, 1H), 7.68 (s, 1H), 7.33 (d,J=8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 6.79-6.77 (m, 1H), 6.75-6.73 (m,1H), 5.09 (s, 2H), 3.39 (s, 3H). Mass (m/z): 416.4 [M+H]⁺.

96 ¹H NMR: (400 Mz, CDCl₃): δ 7.75-7.72 (m, 1H), 7.59 (s, 1H), 7.33 (d,J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 6.79-6.77 (m, 1H), 6.75-6.73 (m,1H), 5.08 (s, 2H), 2.99 (s, 3H). Mass (m/z): 400.6 [M+H]⁺.

3-((3-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrol-1-yl)methyl)benzonitrile(97) and3-((3-(2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrol-1-yl)methyl)benzonitrile(98)

The titled compound 97 (5 mg, 11% yield) and 98 (5 mg, 11% yield) wasprepared as two white solids from 87-01 (30 mg, 0.11 mmol) and3-(bromomethyl)benzonitrile (24 mg, 0.12 mmol) according to theprocedure for 89.

97 ¹H NMR: (400 Mz, CDCl₃): δ 7.77-7.75 (m, 1H), 7.72 (s, 1H), 7.64 (d,J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.42-7.38 (m, 2H), 6.83-6.81 (m,1H), 6.78-6.76 (m, 1H), 5.17 (s, 2H), 3.40 (s, 3H). Mass (m/z): 407.3[M+H]⁺.

98 ¹H NMR: (400 Mz, CDCl₃): δ 7.78-7.75 (m, 1H), 7.63-7.61 (m, 2H),7.51-7.47 (m, 1H), 7.41-7.38 (m, 2H), 6.84-6.82 (m, 1H), 6.77-6.75 (m,1H), 5.17 (s, 2H), 2.99 (s, 3H). Mass (m/z): 391.3 [M+H]⁺.

5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(99)

Step 1. Preparation of4-(6-methoxypyridin-3-yl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine(99-01)

To a solution of 4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine(49-01)(1 g, 4.4 mmol) and (6-methoxypyridin-3-yl)boronic acid (0.8 g,5.3 mmol) in dioxane/H₂O (10 mL/5 mL) was added Pd(PPh₃)₄(250 mg, 0.22mmol) followed by Na₂CO₃ (930 mg, 8.7 mmol) under N₂ atmosphere. Thereaction mixture was refluxed at 90° C. for 5 hrs. The reaction mixturewas cooled to room temperature and filtered over celite. Solvents wereremoved from the filtrate in vacuo, and the residue was extracted by DCMand H₂O 3 times. The organic layer was combined, washed with brine,dried over Na₂SO₄ and further purified by silica gel columnchromatography (PE/EA)=30/1 to give 917 mg of4-(6-methoxypyridin-3-yl)-2-(methylthio)-6-(trifluoromethyl) pyrimidineas a colorless oil (70%). Mass (m/z): 302.05 [M+H]⁺.

Step 2. Preparation of5-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(99-02)

To a solution of4-(6-methoxypyridin-3-yl)-2-(methylthio)-6-(trifluoromethyl)pyrimidine(99-01)(917 mg, 3.05 mmol) in EtOH (10 mL) was added 3 mL HBr(aq)dropwise. The reaction mixture was refluxed at 120° C. for 3 hrs. Thereaction mixture was cooled to room temperature, and alkalized to PH=6.0with statured Na₂CO₃ solution. EtOH was then removed from the mixture byevaporation in vacuo, then the mixture was filtered. The solid part wasdried to give 870 mg of5-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one asa white solid (98%). Mass (m/z): 288.03 [M+H]⁺.

Step 3. Preparation of5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(99)

An aqueous solution of Oxone (5eq) was added dropwise to a solution of5-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(99-02) (100 mg, 0.348 mmol) in MeOH. The reaction mixture was stirredat room temperature for 8 hrs. Solvents were evaporated from thereaction mixture, then the residue was extracted by EtOAc/H₂O 3 times.The organic layer was combined, washed with brine, dried over Na₂SO₄ andfurther purified by silica gel column chromatography (PE/EA=6/1) to give70 mg of5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(99) in a yield of 63% as a white solid. ¹H NMR (400 MHz, CDCl3): δ 8.74(s, 1H), 7.98 (d, J=7.2 Hz, 1H), 7.82 (s, 1H), 7.58 (d, J=7.2 Hz, 1H),3.08 (s, 3H).

5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(prop-2-yn-1-yl)pyridin-2(1H)-one (100) and5-(2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(prop-2-yn-1-yl)pyridin-2(1H)-one (101)

NaH (6 mg, 0.26 mmol) was added to a solution of 99-02 (67 mg, 0.23mmol) in DMF in portions under N₂ atmosphere at 0° C. The reactionmixture was stirred at 0° C. for 30 min, followed by the addition of3-bromoprop-1-yne (30 mg, 0.26 mmol) in portions. The whole reactionmixture was then stirred for 3 hrs at room temperature. The reactionmixture was extracted by EtOAc/H₂O (15 mL/15 mL) 3 times. The organiclayer was combined, washed with brine, dried over Na₂SO₄ and furtherpurified by silica gel column chromatography (PE/EA=1/1) to give5-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(prop-2-yn-1-yl)pyridin-2(1H)-onein a yield of 60% as a white solid (44 mg, 0.14 mmol).

An aqueous solution of Oxone (550 mg, 0.86 mmol) was added dropwise to asolution of5-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(prop-2-yn-1-yl)pyridin-2(1H)-one(40 mg, 0.12 mmol) in MeOH. The reaction mixture was stirred at roomtemperature for 8 hrs. Solvents were evaporated from the reactionmixture, then the residue was extracted by EtOAc/H₂O 3 times. Theorganic layer was combined, washed with brine, dried over Na₂SO₄ andfurther purified by silica gel column chromatography (PE/EA=6/1) to give5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(prop-2-yn-1-yl)pyridin-2(1H)-one(100) in a yield of 65% (28 mg, 0.08 mmol) and5-(2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(prop-2-yn-1-yl)pyridin-2(1H)-one(101) in a yield of 12% (5 mg, 0.01 mmol) two white solids.

100 ¹H NMR (400 Hz, CDCl₃) δ 8.99 (d, J=2.8 Hz, 1H), 8.06 (dd, J=2.8,8.6 Hz, 1H), 7.89 (s, 1H), 6.75 (d, J=9.6 Hz, 1H), 4.88 (d, J=2.8 Hz,2H), 3.45 (s, 3H), 2.65 (t, J=2.8 Hz, 1H)

101 ¹H NMR (400 Hz, CDCl₃) δ 8.97 (d, J=2.4 Hz, 1H), 8.08 (dd, J=2.4,8.6 Hz, 1H), 7.79 (s, 1H), 6.73 (d, J=9.6 Hz, 1H), 4.86 (t, J=1.2 Hz,2H), 3.04 (s, 3H), 2.61 (t, J=2.8 Hz, 1H)

1-(2-azidoethyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one (102)

Step 1. Preparation of1-(2-bromoethyl)-5-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(102-01)

NaH (17 mg, 0.70 mmol) was added to a solution of 99-02 (100 mg, 0.35mmol) in DMF in portions under N₂ atmosphere at 0° C. The reactionmixture was stirred at 0° C. for 30 min, followed by the addition of1,2-dibromoethane (327 mg, 1.74 mmol) in portions. The whole reactionmixture was then stirred for 3 hrs at room temperature. The reactionmixture was extracted by EtOAc/H₂O (15 mL/15 mL) 3 times. The organiclayer was combined, washed with brine, dried over Na₂SO₄ and furtherpurified by silica gel column chromatography (PE/EA=1/1) to give−(2-bromoethyl)-5-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-onein a yield of 32% as alight yellow oil (45 mg, 0.11 mmol).

Step 2. Preparation of1-(2-azidoethyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one (102)

The titled compound 102 (17 mg, 0.04 mmol) was prepared in a yield of40% as a light yellow solid from 102-01 (40 mg, 0.1 mmol) and NaN₃ (66mg, 1 mmol) according to the procedure for 59. ¹H NMR (400 Hz, CDCl₃) δ8.62 (d, J=2.4 Hz, 1H), 8.06 (dd. J=2.4, 9.6 Hz, 1H), 7.89 (s, 1H), 6.73(d, J=9.6 Hz, 1H), 4.21 (t, J=5.6 Hz, 2H), 3.81 (t, J=5.6 Hz, 2H), 3.45(s, 2H).

1-Benzyl-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(103)

Step 1. Preparation of1-Benzyl-5-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one

To a solution of 5-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)pyridine-2(1H)-one (100 mg, 0.32 mmol) in anhydrous DMF (10 mL) wasadded NaH (8.4 mg, 0.35 mmol) at 0° C. and then stirred for 30 min. Thento the mixture was added benzyl bromide (66 mg, 0.38 mmol) and stirredat RT for 5 h. Then the reaction mixture was poured into water andextracted with EA (3×20 mL) and the organic layer was separated, driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby column chromatography (200-300 mesh silica gel, eluted withPE/EtOAc=10:1) to give the product (74 mg, 57%) as a white solid.

Mass (m/z): 378.4 [M+H]⁺.

Step 2. Preparation of1-Benzyl-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one (103)

To a solution of1-benzyl-5-(2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(10 mg, 0.03 mmol) in DCM (2 mL) was added m-CPBA (10 mg, 0.06 mmol) atRT. Then the mixture was stirred at RT for 3 h. The solvent was removedand extracted with DCM (3×15 ml). The organic layer was separated, driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby Pre-TLC (EtOAc/PE=1:2) to obtain 103 as a white solid (4.0 mg, 36%):¹H NMR (400 MHz, CDCl₃): δ 8.65 (d, J=2.8 Hz, 1H), 7.99 (dd, J=2.8, 9.6Hz, 1H), 7.82 (s, 1H), 7.41-7.34 (m, 5H), 6.76 (d, J=9.6 Hz, 1H), 5.27(s, 2H), 3.39 (s, 3H). Mass (m/z): 410.4 [M+H]⁺.

1-(2-chlorobenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(104)

The titled compound 104 (5 mg, 18%) was prepared as a white solid from99-02 (20 mg, 0.07 mmol) and 1-(bromomethyl)-2-chlorobenzene (16 mg,0.08 mmol) according to the procedure for 103.

¹H NMR: (400 Mz, CDCl₃): δ 8.67 (d, J=2.8 Hz, 1H), 8.00 (dd, J=2.8, 9.6Hz, 1H), 7.86 (s, 1H), 7.33-7.30 (m, 3H), 7.25-7.22 (m, 1H), 6.76 (d,J=9.6 Hz, 1H), 5.24 (s, 2H), 3.42 (s, 3H).

Mass (m/z): 444.5 [M+H]⁺.

1-(3-chlorobenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(105)

The titled compound (5 mg, 18%) was prepared as a white solid from 99-02(20 mg, 0.07 mmol) and 1-(bromomethyl)-3-chlorobenzene (16 mg, 0.08mmol) according to the procedure for 103.

¹H NMR: (400 Mz, CDCl₃): δ 8.72 (d, J=2.8 Hz, 1H), 8.01 (dd, J=2.8, 9.6Hz, 1H), 7.81 (s, 1H), 7.45-7.42 (m, 1H), 7.34-7.28 (m, 3H), 6.75 (d,J=9.6 Hz, 1H), 5.37 (s, 2H), 3.38 (s, 3H).

Mass (m/z): 444.4 [M+H]⁺.

1-(4-chlorobenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one106)

The titled compound 106 (6 mg, 21%) was prepared as a white solid from99-02 (20 mg, 0.07 mmol) and 1-(bromomethyl)-4-chlorobenzene (16 mg,0.08 mmol) according to the procedure for 103.

¹H NMR: (400 Mz, CDCl₃): δ 8.69 (d, J=2.4 Hz, 1H), 8.02 (dd, J=2.4, 9.6Hz, 1H), 7.86 (s, 1H), 7.34-7.27 (m, 4H), 6.76 (d, J=9.6 Hz, 1H), 5.24(s, 2H), 3.43 (s, 3H). Mass (m/z): 444.5 [M+H]⁺.

1-(3-bromobenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(107)

The titled compound (5 mg, 15%) was prepared as a white solid from 99-02(20 mg, 0.07 mmol) and 1-(bromomethyl)-3-bromobenzene (20 mg, 0.08 mmol)according to the procedure for 103.

¹H-NMR (400 MHz, CDCl₃): δ 8.67 (d, J=2.8 Hz, 1H), 8.01 (dd, ¹J=2.8 Hz,²J=12.0 Hz, 1H), 7.84 (s, 1H), 7.48-7.46 (m, 2H), 7.29-7.18 (m, 2H),6.77 (d, J=12.0 Hz, 1H), 5.24 (s, 2H), 3.42 (s, 3H).

Mass (m/z): 487.98 [M+H]⁺.

1-(3-hydroxybenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(108)

The titled compound 108 (5 mg, 18%) was prepared as a white solid from99-02 (20 mg, 0.07 mmol) and(3-(bromomethyl)phenoxy)(tert-butyl)dimethylsilane (24 mg, 0.08 mmol)according to the procedure for 103.

¹H NMR (400 Hz, CDCl₃b) δ 8.66 (d, J=2.4 Hz, 1H), 7.97 (dd, J=2.4, 9.6Hz, 1H), 7.83 (s, 1H), 7.24 (d, J=8.0 Hz, 1H), 6.92 (d, J=9.6 Hz, 1H).6.84-6.86 (m, 1H), 6.80-6.83 (m, 1H). 6.74 (d, J=9.6 Hz. 1H), 5.20 (s,2H), 3.41 (s, 3H).

1-(3-methoxybenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(109)

The titled compound (4 mg, 14%) was prepared as a white solid from 99-02(20 mg, 0.07 mmol) and 1-(bromomethyl)-3-methoxybenzene (16 mg, 0.08mmol) according to the procedure for 103.

¹H NMR: (400 Mz, CDCl₃): δ 8.64 (d, J=2.8 Hz, 1H), 8.01 (dd, J=2.8, 9.6Hz, 1H), 7.82 (s, 1H), 7.31-7.26 (m, 1H), 6.92-6.86 (m, 3H), 6.75 (d,J=9.6 Hz, 1H), 5.23 (s, 2H), 3.80 (s, 3H), 3.39 (s, 3H). Mass (m/z):440.2 [M+H]⁺.

1-(4-Methoxybenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(110) and1-(4-Methoxybenzyl)-5-(2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(111)

The titled compound 110 (5 mg, 0.011 mmol) and 111(3 mg, 0.007 mmol) wasprepared in a yield of 11% and 7% as two white solids from 99-02 (30 mg,0.10 mmol) and 1-(chloromethyl)-4-methoxybenzene (22 mg, 0.11 mmol)according to the procedure for 100. For 110, ¹H NMR: (400 Mz, CDCl₃): δ8.63 (d, J=2.0 Hz, 1H), 7.97 (dd, J=2.0, 9.6 Hz, 1H), 7.81 (s, 1H), 7.32(d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 6.73 (d, J=9.6 Hz, 1H), 5.19(s, 2H), 3.79 (s, 3H), 3.39 (s, 3H). Mass (m/z): 440.2 [M+H]⁺. For 111,¹H NMR: (400 Mz, CDCl₃): δ 8.67 (d, J=2.0 Hz, 1H), 7.99 (dd, J=2.0, 9.6Hz, 1H), 7.70 (s, 1H), 7.32 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H),6.72 (d, J=9.6 Hz, 1H), 5.22 (d, J=14.4 Hz, 1H), 5.18 (d, J=14.4 Hz,1H), 3.79 (s, 3H), 3.00 (s, 3H). Mass (m/z): 424.3 [M+H]⁺.

1-(3-ethoxybenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(112)

The titled compound (2 mg) and TC009156(1 mg) was prepared as two whitesolids from 99-02 (20 mg, 0.07 mmol) and 1-(bromomethyl)-3-ethoxybenzene(17 mg, 0.08 mmol) according to the procedure for 103.

¹H NMR (400 Hz, CDCl₃) δ 8.62 (d, J=2.4 Hz, 1H), 7.99 (dd, J=2.4, 9.6Hz, 1H), 7.81 (s, 1H), 7.28 (dd, J=7.6, 8.8 Hz, 1H), 6.84-6.91 (m, 3H),6.75 (d, J=9.6 Hz, 1H), 5.23 (s, 2H), 4.02 (q, J=6.8 Hz, 2H), 3.39 (s,3H), 1.40 (t, J=6.8 Hz, 3H).

5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3-propoxybenzyl)pyridin-2(1H)-one(113) and5-(2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3-propoxybenzyl)pyridin-2(11H)-one(114)

The titled compound 113 (2 mg) and 114 (2 mg) was prepared as two whitesolids from 99-02 (20 mg, 0.07 mmol) and1-(bromomethyl)-3-propoxybenzene (18 mg, 0.08 mmol) according to theprocedure for 103.

113 ¹H NMR (400 Hz, CDCl₃) δ 8.62 (dd, J=2.4 Hz, 1H), 8.00 (dd, J=2.4,9.6 Hz, 1H), 7.81 (s, 1H), 7.15-7.30 (m, 1H), 6.85-6.91 (m, 3H), 6.76(d, J=9.6 Hz, 1H), 5.23 (s, 2H), 3.91 (t. J=6.4 Hzm 2H), 3.39 (s, 3H),1.74-1.84 (m, 2H), 1.22 (t, J=7.6 Hz, 3H). LC-MS (ESI) m/z: calcd for[C₂₁H₂₁F₃N₃O₄S⁺], 468.1, found 469.6.

114 LC-MS (ESI) m/z: calcd for [C₂₁H₂₁F₃N₃O₃S⁺], 452.1, found 452.6.

5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3-(prop-2-yn-1-yloxy)benzyl) pyridin-2(1H)-one (115)

The titled compound (30 mg, 0.02 mmol) was prepared in a yield of 24% asa white solid from 99-02 (30 mg, 0.1 mmol) and1-(bromomethyl)-3-(prop-2-yn-1-yloxy)benzene (80 mg, 0.38 mmol)according to the procedure for 100. ¹H NMR (400 Hz, CDCl₃) δ 8.66 (d,J=2.0 Hz, 1H), 8.03 (dd, J=2.0, 9.6 Hz, 1H), 7.90 (s, 1H), 7.27-7.23 (m,1H), 6.93-6.88 (m, 3H), 6.70 (d, J=9.6 Hz, 1H), 5.19 (s, 2H), 4.63 (dd,J=1.2, 2.4 Hz, 2H), 3.36 (d, J=0.8 Hz, 3H), 2.52 (td, J=2.4, 1.2 Hz,1H).

5-(2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(4-(trifluoromethoxy)benzyl)pyridin-2(1H)-one(116) and5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(4-(trifluoromethoxy)benzyl)pyridin-2(1H)-one(117)

The titled compound 116 (3 mg, 90%) and 117 (2 mg, 6%) was prepared astwo white solids from 99-02 (20 mg, 0.07 mmol) and1-(bromomethyl)-4-(trifluoromethoxy)benzene (20 mg, 0.08 mmol) accordingto the procedure for 103.

116 ¹H NMR: (400 Mz, CDCl₃): δ 8.73 (d, J=2.4 Hz, 1H), 8.00 (dd, J=2.4,9.6 Hz, 1H), 7.73 (s, 1H), 7.38 (d, J=8.0 Hz, 2H), 7.18 (d, J=8.0 Hz,2H), 6.72 (d, J=9.6 Hz, 1H), 5.26 (d, J=14.4 Hz, 1H), 5.22 (d, J=14.4Hz, 1H), 2.99 (s, 3H). Mass (m/z): 478.4 [M+H]⁺.

117 ¹H NMR: (400 Mz, CDCl₃): δ 8.71 (d, J=2.8 Hz, 1H), 7.99 (dd, J=2.8,9.6 Hz, 1H), 7.85 (s, 1H), 7.41 (dd, J=2.8, 8.0 Hz, 2H), 7.21 (d, J=8.0Hz, 2H), 6.75 (d, J=9.6 Hz, 1H), 5.26 (s, 2H), 3.42 (s, 3H). Mass (m/z):478.4 [M+H]⁺.

3-((5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzonitrile(118)

The titled compound (4 mg, 13%) was prepared as a white solid from 99-02(20 mg, 0.07 mmol) and 3-(bromomethyl)benzonitrile (16 mg, 0.08 mmol)according to the procedure for 103.

¹H NMR: (400 Mz, CDCl₃): δ 8.75 (d, J=2.4 Hz, 1H), 8.02 (dd, J=2.0, 9.6Hz, 1H), 7.90 (s, 1H), 7.63-7.50 (m, 4H), 6.77 (d, J=9.6 Hz, 1H), 5.29(s, 2H), 3.43 (s, 3H). Mass (m/z): 435.4 [M+H]⁺.

4-((5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzonitrile(119)

The titled compound (5 mg, 16%) was prepared as a white solid from 99-02(20 mg, 0.07 mmol) and 4-(bromomethyl)benzonitrile (16 mg, 0.08 mmol)according to the procedure for 103.

¹H NMR: (400 Mz, CDCl₃): δ 8.75 (d, J=2.8 Hz, 1H), 8.01 (dd, 0.1=2.8,9.6 Hz, 1H), 7.88 (s, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz,2H), 6.76 (d, J=9.6 Hz, 1H), 5.31 (s, 2H), 3.43 (s, 3H). Mass (m/z):478.4 [M+H]˜.

1-(3-ethynylbenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one (120) and1-(3-ethynylbenzyl)-5-(2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(121)

Step 1. Preparation of (3-ethynylphenyl)methanol (120-01)

To a solution of (3-bromophenyl)methanol (935 mg, 5 mmol) in dry TEA wasadded Pd(PPh₃)₂Cl₂(175 mg, 0.25 mmol), CuI (48 mg, 0.25 mmol) andP(t-Bu)₃(51 mg, 0.25 mmol) under N₂ atmosphere. The reaction mixture wasstirred for 5 mins, followed by addition of ethynyltrimethylsilane(980mg, 10 mmol) dropwise. The reaction mixture was then microwaved at 130°C. for 4 hrs. The reaction mixture was cooled to room temperature,filtered over celite. Solvents were removed from the filtrate in vacuo,then the residue was extracted by EtOAc/H₂O 3 times. The organic layerwas combined, washed with brine, dried over Na₂SO₄ and further purifiedby silica gel column chromatography (PE/EA=4/1) to give 750 mg of(3-((trimethylsilyl)ethynyl)phenyl)methanol as a brown oil (73%).

To a solution of (3-((trimethylsilyl)ethynyl)phenyl)methanol (500 mg,2.46 mmol) in THF was added TBAF (1 g, 4.92 mmol) in portions at 0° C.The reaction mixture was stirred at 0° C. to room temperature for 3 hrs.Solvents were removed from the mixture in vacuo, and the residue wasextracted by EtOAc/H₂O 3 times. The organic layer was combined, washedwith brine, dried over Na₂SO₄ and further purified by silica gel columnchromatography (PE/EA=4/1) to give 184 mg of (3-ethynylphenyl)methanol(120-01) as a brown oil (57%).

Step 2. Preparation of 1-(bromomethyl)-3-ethynylbenzene (120-02)

To a solution of (3-ethynylphenyl)methanol (184 mg, 1.39 mmol) in DCMwas added CBr₄(557 mg, 1.74 mmol) in portions under N₂ atmosphere,followed by the addition of PPh₃(455 mg, 1.74 mmol) in portions afterstirring for 5-10 min. The reaction mixture was stirred at roomtemperature for 3 hrs. Solvents were removed from the reaction mixturein vacuo. The residue was dissolved in EtOAc and filtered. The filtratewas concentrated and further purified by silica gel columnchromatography (PE/EA=30/1) to give 140 mg of1-(bromomethyl)-3-ethynylbenzene as a colorless oil (52%). ¹H NMR (400Hz, CDCl₃) δ 7.51-7.53 (m, 1H), 7.36-7.44 (m, 2H), 7.28-7.32 (m, 1H),4.45 (s, 2H), 3.10 (s, 1H).

Step 3. Preparation of1-(3-ethynylbenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl) pyridin-2(1H)-one (120) and1-(3-ethynylbenzyl)-5-(2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(121)

The titled compound 120 (17 mg, 0.02 mmol) was prepared in a yield of19% as a yellow solid from 99-02 (60 mg, 0.2 mmol) and1-(bromomethyl)-3-ethynylbenzene (120-02) (38 mg, 0.19 mmol) accordingto the procedure for 100. ¹H NMR (400 Hz, CDCl3) δ 8.01 (dd, J=2.8, 9.6Hz, 1H), 7.87 (s, 1H), 7.71 (dd, J=3.2, 6 Hz, 1H), 7.52 (dd, J=3.6, 5.6Hz, 1H), 7.56 (s, 1H), 7.34-7.32 (m, 2H), 6.75 (d, J=9.6 Hz, 1H), 5.34(s, 2H), 3.40 (s, 3H), 3.08 (s, 1H). LC-MS (ESI) m/z: calcd for[C₂₀H₁₅F₃N₃O₃S⁺], 434.0, found 434.0.

The titled compound 121 (18 mg, 0.02 mmol) was prepared in a yield of19% as a yellow solid from 99-02 (60 mg, 0.2 mmol) and1-(bromomethyl)-3-ethynylbenzene (120-02) (38 mg, 0.19 mmol) accordingto the procedure for 100. ¹H NMR (400 Hz, CDCl₃) δ 8.03 (dd, J=2.4, 9.6Hz, 1H), 7.76 (s, 1H), 7.71 (dd, J=3.2, 5.6 Hz, 1H), 7.52 (dd, J=3.2,5.6 Hz, 1H), 7.44 (s, 1H), 7.36-7.30 (m, 2H), 6.75 (d, J=9.6 Hz, 1H),5.24 (dd, J=14.4, 21.2 Hz, 2H), 3.08 (s, 1H), 3.01 (s, 3H). LC-MS (ESI)m/z: calcd for [C₂₀H₁₅F₃N₃O₂S⁺], 418.1, found 418.1.

1-(4-ethynylbenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(122)

Step 1. Preparation of (4-ethynylphenyl)methanol (122-01)

To a solution of (4-bromophenyl)methanol (935 mg, 5 mmol) in dry TEA wasadded Pd(PPh₃)₂Cl₂(175 mg, 0.25 mmol), CuI (48 mg, 0.25 mmol) andP(t-Bu)₃(51 mg, 0.25 mmol) under N₂ atmosphere. The reaction mixture wasstirred for 5 mins, followed by addition of ethynyltrimethylsilane(980mg, 10 mmol) dropwise. The reaction mixture was then microwaved at 130°C. for 4 hrs. The reaction mixture was cooled to room temperature,filtered over celite. Solvents were removed from the filtrate in vacuo,then the residue was extracted by EtOAc/H₂O 3 times. The organic layerwas combined, washed with brine, dried over Na₂SO₄ and further purifiedby silica gel column chromatography (PE/EA=4/1) to give 670 mg of(4-((trimethylsilyl)ethynyl)phenyl)methanol as a brown oil (66%).

To a solution of (4-((trimethylsilyl)ethynyl)phenyl)methanol (250 mg,1.23 mmol) in THF was added TBAF (500 mg, 2.45 mmol) in portions at 0°C. The reaction mixture was stirred at 0° C. to room temperature for 3hrs. Solvents were removed from the mixture in vacuo, and the residuewas extracted by EtOAc/H₂O 3 times. The organic layer was combined,washed with brine, dried over Na₂SO₄ and further purified by silica gelcolumn chromatography (PE/EA=4/1) to give 170 mg of(4-ethynylphenyl)methanol as a brown oil (100%). ¹H NMR (400 Hz, CDCl3)S 7.45-7.49 (m, 2H), 7.21-7.26 (m, 2H), 4.69 (s, 1H), 4.65 (s, 2H).

Step 2. Preparation of 1-(bromomethyl)-4-ethynylbenzene (122-02)

To a solution of (4-ethynylphenyl)methanol (110 mg, 0.84 mmol) in dryDCM was added PBr₃(450 mg, 1.67 mmol) dropwise at 0° C. The reactionmixture was stirred at 0° C. to room temperature for 3 hrs. The reactionwas quenched by H₂O, then extracted by DCM/H₂O 3 times. The organiclayer was combined, washed with brine, dried over Na₂SO₄ and furtherpurified by silica gel column chromatography (PE/EA=10/1) to give 80 mgof 1-(bromomethyl)-4-ethynylbenzene as a colorless oil (50%). ¹H NMR(400 Hz, CDCl₃) δ 7.45-7.48 (m, 2H), 7.33-7.36 (m, 2H), 4.47 (s, 2H),3.13 (s, 1H).

Step 3. Preparation of1-(4-ethynylbenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl) pyridin-2(1H)-one (122)

The titled compound (120 mg, 0.26 mmol) was prepared in a yield of 64%as a yellow solid from 99-02 (130 mg, 0.45 mmol) and1-(bromomethyl)-4-ethynylbenzene (122-02) (80 mg, 0.41 mmol) accordingto the procedure for 100. ¹H NMR (400 Hz, CDCl3) δ 8.68 (d, J=2.4 Hz,1H), 8.00 (dd, J=2.4, 9.6 Hz, 1H), 7.88 (s, 1H), 7.45 (d, J=8.0 Hz, 2H),7.29 (d, J=8.0 Hz, 2H), 6.72 (d, J=9.6 Hz, 1H), 5.23 (s, 2H), 3.39 (s,3H), 3.08 (s, 1H). LC-MS (ESI) m/z: calcd for [C₂₀H₁₅F₃N₃O₃S⁺], 434.0,found 434.1.

1-(4-azidobenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(123)

The titled compound (13 mg, 0.029 mmol) was prepared in a yield of 29%as a yellow solid from 99-02 (46 mg, 0.10 mmol) and1-azido-4-(bromomethyl)benzene (44 mg, 0.21 mmol) according to theprocedure for 100. ¹H NMR (400 Hz, CDCl3) δ 8.70 (d, J=2.8 Hz, 1H), 7.98(dd, J=2.8, 9.6 Hz, 1H), 7.83 (s, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.03 (d,J=8.4 Hz, 2H), 6.75 (d, J=9.6 Hz, 1H), 5.23 (s, 2H), 3.42 (s, 3H).

1-(4-chloro-2-fluorobenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(124) and1-(4-chloro-2-fluorobenzyl)-5-(2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(125)

The titled compound 124 (3 mg, 9%) and 125 (2 mg, 6%) was prepared astwo white solids from 99-02 (20 mg, 0.07 mmol) and1-(bromomethyl)-4-chloro-2-fluorobenzene (18 mg, 0.08 mmol) according tothe procedure for 103.

124 ¹H NMR: (400 Mz, CDCl₃): δ 8.76 (d, J=2.8 Hz, 1H), 8.02 (dd, J=2.8,9.6 Hz, 1H), 7.87 (s, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.16-7.12 (m, 2H),6.71 (d, J=9.6 Hz, 1H), 5.24 (s, 2H), 3.43 (s, 3H). Mass (m/z): 462.5[M+H]⁺.

125 ¹H NMR: (400 Mz, CDCl₃): δ 8.79 (d, J=2.8 Hz, 1H), 8.04 (dd, J=2.4,9.6 Hz, 1H), 7.75 (s, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.15-7.12 (m, 2H),6.70 (d, J=9.6 Hz, 1H), 5.27 (d, J=14.4 Hz, 1H), 5.22 (d, J=14.4 Hz,1H), 3.03 (s, 3H). Mass (m/z): 446.3 [M+H]⁺.

1-(2-chloro-4-methoxybenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(126)

The titled compound 126 (5 mg, 15%) was prepared as a white solid from99-02 (20 mg, 0.07 mmol) and 1-(bromomethyl)-2-chloro-4-methoxybenzene(20 mg, 0.08 mmol) according to the procedure for 103.

¹H NMR: (400 Mz, CDCl₃): δ 8.73 (d, J=2.8 Hz, 1H), 8.00 (dd, J=2.8, 9.6Hz, 1H), 7.81 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 6.98 (d, J=2.8 Hz, 1H),6.83 (d, J=2.4, 8.4 Hz, 1H), 6.73 (d, J=9.6 Hz, 1H), 5.30 (s, 2H), 3.81(s, 3H), 3.39 (s, 3H). Mass (m/z): 474.3 [M+H]⁺.

1-(3,4-dimethoxybenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(127) and1-(3,4-dimethoxybenzyl)-5-(2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(128)

The titled compound 127 (6 mg, 15%) and 128 (4 mg, 10%) was prepared astwo white solids from 99-02 (20 mg, 0.07 mmol) and4-(bromomethyl)-1,2-dimethoxybenzene (19 mg, 0.08 mmol) according to theprocedure for 103.

127 ¹H NMR: (400 Mz, CDCl₃): δ 8.68 (d, J=2.4 Hz, 1H), 7.98 (dd, J=2.4,9.6 Hz, 1H), 7.82 (s, 1H), 6.94 (s, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.84(d, J=8.0 Hz, 1H), 6.73 (d, J=9.6 Hz, 1H), 5.18 (s, 2H), 3.87 (s, 3H),3.85 (s, 3H), 3.38 (s, 3H). Mass (m/z): 470.3 [M+H]⁺.

128 ¹H NMR: (400 Mz, DMSO-d6): δ 9.24 (d, J=2.8 Hz, 1H), 8.68 (s, 1H),8.41 (dd, J=2.4, 9.6 Hz, 1H), 7.10 (d, J=2.8 Hz, 1H), 6.92 (d, J=8.4 Hz,1H), 6.88 (dd, J=2.4, 8.4 Hz, 1H), 6.63 (d, J=9.6 Hz, 1H), 5.18 (s, 2H),3.73 (s, 3H), 3.72 (s, 3H), 3.53 (s, 3H). Mass (m/z): 454.3 [M+H]⁺.

1-(4-methoxy-3-(prop-2-yn-1-yloxy)benzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(129)

Step 1. Preparation of 4-methoxy-3-(prop-2-yn-1-yloxy)benzaldehyde(129-01)

K₂CO₃(1.1 g, 8.0 mmol) was added to a solution of3-hydroxy-4-methoxybenzaldehyde (1 g, 6.6 mmol) and 3-bromoprop-1-yne(0.95 g, 7.9 mmol) in DMF (10 mL). The reaction mixture was stirred atroom temperature for 3 hrs. The reaction mixture was extracted by EtOAcand H₂O 3 times. The organic layer was combined, washed with brine,dried over Na₂SO₄, concentrated and further purified by silica gelcolumn chromatography (PE/EA=4/1), to give 1.24 g of4-methoxy-3-(prop-2-yn-1-yloxy)benzaldehyde as a yellow oil (100%). ¹HNMR (400 Hz, CDCl3) δ 7.50-7.53 (m, 2H), 7.00 (d, J=8.0 Hz, 1H), 4.81(d, J=2.4 Hz, 2H), 3.95 (s, 3H), 2.53-2.55 (t, J=2.4 Hz, 1H).

Step 2. Preparation of (4-methoxy-3-(prop-2-yn-1-yloxy)phenyl)methanol(129-02)

To a solution of 4-methoxy-3-(prop-2-yn-1-yloxy)benzaldehyde(129-01)(1.24 g, 6.5 mmol) in anhydrous MeOH (15 mL) was added NaBH₄(350mg, 8.8 mmol) in portions at 0° C. under N₂ atmosphere. The reactionmixture was then stirred at 0° C. to room temperature for 3 hrs. Thereaction was quenched by H₂O, then the solvents were removed from themixture invacuo. The residue was extracted by EtOAc and H₂O 3 times. Theorganic layer was combined, washed with brine, dried over Na₂SO₄,concentrated and further purified by silica gel column chromatography(PE/EA=1/1) to give 1.07 g of(4-methoxy-3-(prop-2-yn-1-yloxy)phenyl)methanol as a white solid (75%).¹H NMR (400 Hz, CDCl3) δ 7.07 (d, J=2.0 Hz, 1H), 6.97 (dd, J=2.0, 8.0Hz, 1H), 4.78 (d, J=2.4 Hz, 2H), 4.63 (d, J=5.6 Hz, 2H), 3.87 (s, 3H),2.51 (t, J=2.4 Hz, 1H).

Step 3. Preparation of4-(bromomethyl)-1-methoxy-2-(prop-2-yn-1-yloxy)benzene (129-03)

To a solution of (4-methoxy-3-(prop-2-yn-1-yloxy)phenyl)methanol(129-02) (200 mg, 1.04 mmol) in DCM was added CBr₄(432 mg, 1.30 mmol) inportions under N₂ atmosphere, followed by the addition of PPh₃(341 mg,1.30 mmol) in portions after stirring for 5-10 min. The reaction mixturewas stirred at room temperature for 3 hrs. Solvents were removed fromthe reaction mixture in vacuo. The residue was dissolved in EtOAc andfiltered. The filtrate was concentrated and further purified by silicagel column chromatography (PE/EA=10/1) to give 221 mg of4-(bromomethyl)-1-methoxy-2-(prop-2-yn-1-yloxy)benzene (83%). ¹H NMR(400 Hz, CDCl3) δ 7.06-7.08 (m, 1H), 6.99-7.03 (m, 1H), 6.82-6.85 (m,1H), 4.76-4.78 (m, 2H), 4.49 (s, 2H), 3.87 (s, 3H), 2.53 (t, J=2.4 Hz,1H).

Step 4. Preparation of1-(4-methoxy-3-(prop-2-yn-1-yloxy)benzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(129)

The titled compound 129 (24 mg, 0.04 mmol) was prepared in a yield of13% as a white solid from 99-02 (74 mg, 0.29 mmol) and4-(bromomethyl)-1-methoxy-2-(prop-2-yn-1-yloxy)benzene (129-03) (57 mg,0.29 mmol) according to the procedure for 100. ¹H NMR (400 Hz, CDCl3) δ8.67 (d, J=2.8 Hz, 1H), 7.96 (dd, J=2.8, 9.6 Hz, 1H), 7.82 (s, 1H), 7.10(d, J=2.0 Hz, 1H), 7.01 (dd, J=2.0, 8.4 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H),6.74 (d, J=9.6 Hz, 1H), 5.20 (s, 2H), 4.76 (d, J=2.0 Hz, 2H), 3.88 (s,3H), 43.46 (s, 3H), 2.55 (t, J=2.0 Hz, 1H). LC-MS (ESI) m/z: calcd for[C₂₂H₁₉F₃N₃O₅S⁺], 494.1, found 494.3.

1-(3-methoxy-4-(prop-2-yn-1-yloxy)benzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(130)

Step 1. Preparation of (3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)methanol(130-01)

To a solution of 4-(hydroxymethyl)-2-methoxyphenol (770 mg, 4.6 mmol) inacetone was added K₂CO₃(1.04 g, 5.5 mmol) and KI (910 mg, 5.5 mmol),followed by addition of 3-bromoprop-1-yne (650 mg, 5 mmol). The reactionmixture was refluxed at 75° C. for 8 hrs. The reaction mixture wascooled to room temperature, and solvents were removed in vacuo. Theresidue was extracted by EtOAc and H₂O 3 times. The organic layer wascombined, washed with brine, dried over Na₂SO₄, concentrated and furtherpurified by silica gel column chromatography (PE/EA=4/1), to give 725 mgof (3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)methanol as a yellow oil(182%).

Step 2. Preparation of4-(bromomethyl)-2-methoxy-1-(prop-2-yn-1-yloxy)benzene (130-02)

To a solution of (3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)methanol(130-01) (422 mg, 2.2 mmol) in DCM was added CBr₄(910 mg, 2.7 mmol) inportions under N₂ atmosphere, followed by the addition of PPh₃(720 mg,2.70 mmol) in portions after stirring for 5-10 min. The reaction mixturewas stirred at room temperature for 3 hrs. Solvents were removed fromthe reaction mixture in vacuo. The residue was dissolved in EtOAc andfiltered. The filtrate was concentrated and further purified by silicagel column chromatography (PE/EA=10/1) to give 420 mg of4-(bromomethyl)-2-methoxy-1-(prop-2-yn-1-yloxy)benzene (75%). δ¹H NMR(400 Hz, CDCl3) δ 6.94-6.99 (m, 3H), 4.76-4.78 (m, 2H), 4.50 (s, 2H),3.89 (s, 3H), 2.51-2.52 (m, 1H).

Step 3. Preparation of1-(3-methoxy-4-(prop-2-yn-1-yloxy)benzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(130)

The tided compound 130 (5 mg, 0.01 mmol) was prepared in a yield of 5%as a white solid from 99-02 (65 mg, 0.23 mmol) and4-(bromomethyl)-2-methoxy-1-(prop-2-yn-1-yloxy)benzene (130-02) (54 mg,0.23 mmol) according to the procedure for 100. δ¹H NMR (400 Hz, CDCl3) δ8.69 (d, J=2.4 Hz, 1H), 7.98 (dd, J=2.4, 9.6 Hz, 1H), 7.83 (s, 1H), 7.02(d, J=8.0 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.75 (d, J=9.6Hz, 1H), 5.20 (s, 2H), 4.76 (d, J=2.4 Hz, 2H), 3.87 (s, 3H), 3.40 (s,3H), 2.51 (t, J=2.4 Hz, 1H). LC-MS (ESI) m/z: calcd for[C₂₂H₁₉F₃N₃O₅S⁺], 494.1, found 494.0.

1-([1,1′-biphenyl]-4-ylmethyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(131)

The titled compound (7 mg, 0.015 mmol) was prepared in a yield of 42% asa white solid from 99-02 (10 mg, 0.04 mmol) and4-(bromomethyl)-1,1′-biphenyl (12 mg, 0.05 mmol) according to theprocedure for 100. ¹H-NMR: (400 Mz, CDCl3): δ 8.72 (d, J=2.4 Hz, 1H),8.01 (dd, ¹J=2.4 Hz, ²J=10 Hz, 1H), 7.85 (s, 1H), 7.59-7.34 (m, 4H),7.44-7.41 (m, 4H), 7.36-7.33 (m, 1H), 6.75 (d, J=10 Hz, 1H), 5.29 (s,2H), 3.37 (s, 3H). Mass (m/z): 486.10[M+H]⁺.

1-(4-(1H-pyrazol-1-yl)benzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(132)

The titled compound (18 mg, 0.038 mmol) was prepared in a yield of 35%as a white solid from 99-02 (30 mg, 0.11 mmol) and1-(4-(bromomethyl)phenyl)-1H-pyrazole (36 mg, 0.15 mmol) according tothe procedure for 100. ¹H-NMR (400 MHz, CDCl₃): δ 8.72 (d, J=2.0 Hz,1H), 7.99 (m, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.86 (s, 1H), 7.72-7.69 (m,3H), 7.46 (d, J=9.2 Hz, 2H), 6.75 (d, J=9.2 Hz, 1H), 6.46 (m, 1H), 5.29(s, 3H), 3.40 (s, 1H). Mass (m/z): 476.09 [M+H]⁺.

5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(naphthalen-1-ylmethyl)pyridin-2(1H)-one(133)

The titled compound (5 mg, 16%) was prepared as a white solid from 99-02(20 mg, 0.07 mmol) and 1-(bromomethyl)naphthalene (18 mg, 0.08 mmol)according to the procedure for 103. ¹H NMR: (400 Mz, CDCl₃): δ 8.43 (d,J=9.6 Hz, 1H), 8.02-7.91 (m, 4H), 7.68 (s, 1H), 7.58-7.42 (m, 4H), 6.83(d, J=9.6 Hz, 1H), 5.72 (s, 2H), 3.18 (s, 3H). Mass (m/z): 460.3 [M+H]⁺.

5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(naphthalen-2-ylmethyl)pyridin-2(1H)-one(134)

The titled compound (5 mg, 16%) was prepared as a white solid from 99-02(20 mg, 0.07 mmol) and 2-(bromomethyl)naphthalene (18 mg, 0.08 mmol)according to the procedure for 103. ¹H NMR: (400 Mz, CDCl₃): δ 8.68 (d,J=2.4 Hz, 1H), 8.00 (dd, J=2.4, 9.6 Hz, 1H), 7.87-7.81 (m, 4H),7.52-7.45 (m, 4H), 6.78 (d, J=9.6 Hz, 1H), 5.43 (s, 2H), 3.29 (s, 3H).Mass (m/z): 460.3 [M+H]⁺.

1-((2-methoxypyridin-4-yl)methyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(135)

The titled compound (2 mg, 6%) was prepared as a white solid from 99-02(20 mg, 0.07 mmol) and 4-(bromomethyl)-2-methoxypyridine (16 mg, 0.08mmol) according to the procedure for 103. ¹H NMR (400 Hz, CDCl₃) δ8.69-8.70 (m, 1H), 8.16 (d, J=5.6 Hz, 1H), 8.04 (dd, J=2.4, 9.6 Hz, 1H).7.88 (s. 1H), 6.82 (d, J=5.2 Hz, 1H), 6.79 (d, J=9.6 Hz, 1H). 5.24 (s.2H), 3.95 (s, 3H), 3.43 (s, 3H).

1-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(136)

The titled compound (2 mg, 6%) was prepared as two white solid from99-02 (20 mg, 0.07 mmol) and 5-(bromomethyl)benzo[d][1,3]dioxole (17 mg,0.08 mmol) according to the procedure for 103.

¹H NMR (400 Hz, CDCl₃) δ 8.63 (d, J=2.4 Hz, 1H), 7.98 (dd, J=2.4, 9.6Hz, 1H), 7.82 (s, 1H), 6.84-6.86 (m, 2H), 6.80 (d, J=8.4 Hz, 1H), 6.74(d, J=9.6 Hz, 1H), 5.96 (s, 2H), 5.16 (s, 2H), 3.41 (s, 3H). LC-MS (ESI)m/z: calcd for [C₁₉H₁₅F₃N₃O₅S⁺], 454.1, found 454.5.

1-((4-bromobenzo[d][1,3]dioxol-5-yl)methyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(137) and1-((4-bromobenzo[d][1,3]dioxol-5-yl)methyl)-5-(2-(methylsulfinyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(138)

The titled compound 137 (5 mg, 13%) and 138 (4 mg, 100%) were preparedas two white solid from 99-02 (20 mg, 0.07 mmol) and4-bromo-5-(bromomethyl)benzo[d][1,3]dioxole (24 mg, 0.08 mmol) accordingto the procedure for 103.

137 ¹H NMR: (400 Mz, CDCl₃): δ 8.78 (d, J=2.8 Hz, 1H), 8.02 (dd, J=2.8,9.6 Hz, 1H), 7.83 (s, 1H), 7.06 (s, 1H), 6.88 (s, 1H), 6.75 (d, J=9.6Hz, 1H), 5.99 (s, 2H), 5.28 (s, 2H), 3.40 (s, 3H). Mass (m/z): 533.3[M+H]⁺.

138 ¹H NMR: (400 Mz, CDCl₃): δ 8.80 (d, J=2.8 Hz, 1H), 8.05 (dd, J=2.8,9.6 Hz, 1H), 7.73 (s, 1H), 7.06 (s, 1H), 6.85 (s, 1H), 6.74 (d, J=9.6Hz, 1H), 5.98 (s, 2H), 5.29 (d, J=14.8 Hz, 1H), 5.25 (d, J=14.8 Hz, 1H),3.01 (s, 3H). Mass (m/z): 517.3 [M+H]⁺.

1-(3,4-dimethoxybenzyl)-5-(2-(methylsulfonyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)pyridin-2(1H)one (139)

Step 1. Preparation of4-chloro-2-(methylthio)-6-(1H-pyrazol-1-yl)pyrimidine (139-01)

The titled compound 139-01 was prepared in a yield of 40% (130 mg, 0.56mmol) as a white solid from 4,6-dichloro-2-(methylthio)pyrimidine (300mg, 1.55 mmol) and 1H-pyrazole (95 mg, 1.40 mmol) according to theprocedure for 36.

Step 2. Preparation of4-(6-methoxypyridin-3-yl)-2-(methylthio)-6-(1H-pyrazol-1-yl)pyrimidine(139-02)

The titled compound 139-02 was prepared in a yield of 86% (146 mg, 0.47mmol) as a white solid from 139-01 (125 mg, 0.55 mmol) and2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (140mg, 0.61 mmol) according to the procedure for 99-01.

Step 3. Preparation of5-(2-(methylthio)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)pyridin-2(1H)-one(139-03)

The titled compound 139-03 was prepared in a yield of 54% (75 mg, 0.30mmol) as a white solid from 139-02 (146 mg, 0.47 mmol) according to theprocedure for 99-02.

Step 4. preparation of1-(3,4-dimethoxybenzyl)-5-(2-(methylsulfonyl)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)pyridin-2(1H)-one(139)

The titled compound 139 was prepared in a yield of 14% (10 mg, 0.02mmol) as a white solid from 139-03 (40 mg, 0.14 mmol) and4-(bromomethyl)-1,2-dimethoxybenzene (32 mg, 0.14 mmol) according to theprocedure for 99-01. ¹H NMR (400 Hz, CDCl₃) δ 8.62 (d, J=2.4 Hz, 1H),8.53 (d, J=2.4 Hz, 1H), 8.15 (s, 1H), 8.04 (dd, J=2.4, 9.6 Hz, 1H), 7.85(d, J=0.8 Hz, 1H), 6.95-6.97 (m, 1H), 6.93 (d, J=2.4 Hz, 1H), 6.85-6.88(m, 1H), 6.73 (d, J=9.6 Hz, 1H), 6.57 (dd, J=1.6, 2.4 Hz, 1H), 5.19 (s,2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.35 (s, 3H). LC-MS (ESI) m/z: calcdfor [C₂₂H₂₂N₅O₅S⁺], 468.1, found 468.5.

5-(2-(([1,1′-biphenyl]-4-ylmethyl)sulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(140)

Preparation of1-(3,4-dimethoxybenzyl)-5-(2-mercapto-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(140-01)

NaHS (28 mg, 0.38 mmol) was added to a solution of1-(3,4-dimethoxybenzyl)-5-(2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(130) (60 mg, 0.13 mmol) in DMF (2 mL) under N₂ atmosphere. The reactionmixture was stirred at room temperature for 2 hrs. The reaction mixturewas acidified to PH=5 by 1N HCl, then extracted by DCM/H₂O. The organiclayer was combined, washed with brine, dried over Na₂SO₄ and furtherpurified by silica gel column chromatography (PE/EA=1/1) to give 50 mgof1-(3,4-dimethoxybenzyl)-5-(2-mercapto-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-oneas a yellow solid (98%).

Preparation of5-(2-(([1,1′-biphenyl]-4-ylmethyl)sulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one

K₂CO₃(10 mg, 0.07 mmol) was added to a solution of1-(3,4-dimethoxybenzyl)-5-(2-mercapto-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(20 mg, 0.05 mmol) and 4-(chloromethyl)-1,1′-biphenyl (15 mg, 0.07 mmol)in DMF (2 mL). The reaction mixture was stirred at room temperature for3 hrs. The reaction mixture was extracted by EtOAc and H₂O 3 times. Theorganic layer was combined, washed with brine, dried over Na₂SO₄,concentrated and further purified by silica gel column chromatography(PE/EA=4/1), to give 10 mg of5-(2-(([1,1′-biphenyl]-4-ylmethyl)thio)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-oneas a white solid (36%).

An aqueous solution of Oxone (50 mg, 0.08 mmol) was added dropwise to asolution of5-(2-(([1,1′-biphenyl]-4-ylmethyl)thio)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(10 mg, 0.02 mmol) in MeOH (2 mL). The reaction mixture was stirred atroom temperature for 8 hrs. Solvents were evaporated from the reactionmixture, then the residue was extracted by EtOAc/H₂O 3 times. Theorganic layer was combined, washed with brine, dried over Na₂SO₄ andfurther purified by silica gel column chromatography (PE/EA=10/1) togive 2 mg of5-(2-(([1,1′-biphenyl]-4-ylmethyl)sulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-oneas a white solid (16%). LC-MS (ESI) m-z: calcd for [C₃₂H₂₇F₃N₃O₅S₃ ⁺],622.2, found 622.4.

5-(2-(but-3-yn-1-ylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(141)

The titled compound was prepared in a yield of 15% (7 mg, 0.015 mmol) asa white solid from 140-01(40 mg, 0.10 mmol) and 4-bromobut-1-yne (20 mg,0.14 mmol) according to the procedure for 140. ¹H NMR (400 Hz, CDCl₃) δ8.68 (d, J=2.4 Hz, 1H), 7.96 (dd, J=1.2, 9.6 Hz, 1H), 7.82 (s, 1H),6.96˜6.92 (m, 2H), 6.85 (d, J=8.0 Hz, 1H), 6.73 (d, J=9.6 Hz, 1H), 5.19(s, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.79 (t, J=7.2 Hz, 2H), 2.85 (dt,J=7.2, 2.8 Hz, 2H), 1.97 (t, J=2.8 Hz, 1H).

1-(3,4-dimethoxybenzyl)-5-(6-(trifluoromethyl)-2-(vinylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(142)

The title compound was prepared in a yield of 69% (40 mg, 0.12 mmol) asa colorless oil from 140-01 (50 mg, 0.12 mmol) and2-bromo-N,N-dimethylethanamine (0.18 mmol) according to the procedurefor 140. 142: ¹HNMR (400 MHz, CDCl₃) δ 8.45 (d, J=2.8 Hz, 1H), 7.99 (dd,J=2.8, 9.6 Hz, 1H), 7.83 (s, 1H), 7.09 (dd, J=10.0, 16.4 Hz, 1H),6.93-6.90 (m, 2H), 6.84 (d, J=8.4 Hz, 1H), 6.72 (d, J=9.6 Hz, 1H), 6.69(d, J=17.2 Hz, 1H), 6.37 (d, J=10.0 Hz, 1H), 5.17 (s, 2H), 3.85 (s, 3H),3.84 (s, 3H). Mass (m/z): 482.54 [M+H]⁺.

1-(3,4-dimethoxybenzyl)-5-(2-((2-methoxyethyl)sulfonyl)-6-trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(143)

The titled compound was prepared in a yield of 68% (21 mg, 0.041 mmol)as a white solid from 140-01(24 mg, 0.06 mmol) and1-bromo-2-methoxyethane (12 mg, 0.09 mmol) according to the procedurefor 140. ¹HNMR (400 MHz, CDCl₃) δ 8.68 (d, J=2.8 Hz, 1H), 8.01 (dd,J=2.8, 9.6 Hz, 1H), 7.81 (s, 1H), 6.95-6.92 (m, 2H), 6.85 (d, J=8.0 Hz,1H), 6.75 (d, J=9.6 Hz, 1H), 5.19 (s, 2H), 3.59-3.85 (m, 8H), 3.80 (t,J=5.6 Hz, 2H), 3.16 (s, 3H). Mass (m/z): 514.43 [M+H]⁺.

1-(3,4-dimethoxybenzyl)-5-(2-((3-methoxypropyl)sulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(144)

The titled compound was prepared in a yield of 80% (21 mg, 0.04 mmol) asa white solid from 140-01(21 mg, 0.05 mmol) and 1-bromo-3-methoxypropane(11 mg, 0.075 mmol) according to the procedure for 140. ¹HNMR (400 MHz,CDCl₃) δ 8.70 (d, J=2.4 Hz, 1H), 7.99 (dd, J=2.4, 9.6 Hz, 1H), 7.81 (s,1H), 6.96-6.91 (m, 2H), 6.85 (d, J=8.4 Hz, 1H), 6.74 (d, J=9.6 Hz, 1H),5.19 (s, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.69 (t, J=7.6 Hz, 2H), 3.52(t, J=5.6 Hz, 2H), 3.30 (s, 3H), 2.21-2.14 (m, 2H). Mass (m/z): 528.49[M+H]⁺.

1-(3,4-dimethoxybenzyl)-5-(2-((2-(2-methoxyethoxy)ethyl)thio)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(145)

The titled compound was prepared in a yield of 71% (17 mg, 0.03 mmol) asa white solid from 140-01(18 mg, 0.042 mmol) and1-bromo-2-(2-methoxyethoxy)ethane (12 mg, 0.063 mmol) according to theprocedure for 140. ¹HNMR (400 MHz, CDCl₃) δ 8.66 (d, J=2.8 Hz, 1H), 7.99(dd, J=2.8, 9.6 Hz, 1H), 7.79 (s, 1H), 6.95-6.92 (m, 2H), 6.86 (d, J=8.0Hz, 1H), 6.75 (d, J=9.6 Hz, 1H), 5.19 (s, 2H), 3.97 (t, J=6.0 Hz, 2H),3.87-3.83 (m, 8H), 3.45-3.43 (m, 2H), 3.23-3.20 (m, 2H), 3.14 (s, 3H).Mass (m/z): 558.25 [M+H]⁺.

1-(3,4-dimethoxybenzyl)-5-(2-(heptylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(146)

The titled compound was prepared in a yield of 46% (13 mg, 0.023 mmol)as a white solid from 140-01(21 mg, 0.05 mmol) and1-bromo-3-methoxypropane (11 mg, 0.075 mmol) according to the procedurefor 140. ¹HNMR (400 MHz, CDCl3) δ 8.69 (d, J=2.4 Hz, 1H), 7.98 (dd,J=2.8, 9.6 Hz, 1H), 7.79 (s, 1H), 6.94-6.90 (m, 2H), 6.84 (dm J=8.4 Hz,1H), 6.75 (d, J=9.6 Hz, 1H), 5.19 (s, 2H), 3.86 (s, 3H), 3.85 (s, 3H),3.56 (t, J=8.0 Hz, 2H), 1.90-1.84 (m, 2H), 1.34-1.24 (m, 6H), 0.86 (t,J=6.8 Hz, 3H). Mass (m/z): 554.27 [M+H]⁺

1-(3,4-dimethoxybenzyl)-5-(2-(pentylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(147)

The titled compound was prepared in a yield of 77% (21 mg, 0.04 mmol) asa white solid from 140-01(22 mg, 0.052 mmol) and 1-bromopentane (12 mg,0.078 mmol) according to the procedure for 140. Mass (m/z): 526.20[M+H]⁺.

1-(3,4-dimethoxybenzyl)-5-(2-((2-(2-methoxyethoxy)ethyl)sulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(148)

The titled compound was prepared in a yield of 74% (17 mg, 0.031 mmol)as a light yellow oil from 140-01(18 mg, 0.042 mmol) and1-bromo-2-(2-methoxyethoxy)ethane (12 mg, 0.063 mmol) according to theprocedure for 140. ¹HNMR (400 MHz, CDCl₃) δ 8.66 (d, J=2.8 Hz, 1H), 7.99(dd, J=2.8, 9.6 Hz, 1H), 7.79 (s, 1H), 6.95-6.92 (m, 2H), 6.86 (d, J=8.0Hz, 1H), 6.75 (d, J=9.6 Hz, 1H), 5.19 (s, 2H), 3.97 (t, J=6.0 Hz, 2H),3.87-3.83 (m, 8H), 3.45-3.43 (m, 2H), 3.23-3.20 (m, 2H), 3.14 (s, 3H).Mass (m/z): 558.25 [M+H]⁺.

3-((4-(1-(3,4-dimethoxybenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl)sulfonyl)-N,N-dimethylpropanamide(149)

The titled compound was prepared in a yield of 23% (6 mg, 0.011 mmol) asa white solid from 140-01(20 mg, 0.047 mmol) and3-bromo-N,N-dimethylpropanamide (13 mg, 0.071 mmol) according to theprocedure for 140. ¹HNMR (400 MHz, CDCl₃) δ 8.75 (d, J=2.4 Hz, 1H), 8.01(dd, J=2.8, 9.6 Hz, 1H), 7.82 (s, 1H), 6.98-6.94 (m, 2H), 6.86 (d, J=8.0Hz, 1H), 6.80 (d, J=9.6 Hz, 1H), 5.22 (s, 2H), 3.96 (t, J=7.2 Hz, 2H),3.87 (s, 3H), 3.86 (s, 3H), 3.04-3.00 (m, 5H), 2.93 (s, 3H). Mass (m/z):555.24 [M+H]⁺.

1-(3,4-dimethoxybenzyl)-5-(2-((3-oxo-3-(pyrrolidin-1-yl)propyl)sulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(150)

The titled compound was prepared in a yield of 49% (17 mg, 0.029 mmol)as a colorless syrup from 140-01(25 mg, 0.059 mmol) and3-bromo-1-(pyrrolidin-1-yl)propan-1-one (24 mg, 0.12 mmol) according tothe procedure for 140. ¹HNMR (400 MHz, CDCl₃) δ 8.77 (d, J=2.8 Hz, 1H),7.99 (dd, J=2.8, 9.6 Hz, 1H), 7.83 (s, 1H), 6.98 (d, J=2.0 Hz, 1H), 6.96(dd, J=2.0, 8.4 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.72 (d, J=9.6 Hz, 1H),5.20 (s, 2H), 3.96 (t, J=7.6 Hz, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 3.40(q, J=6.7 Hz, 4H), 2.92 (t, J=7.6 Hz, 2H), 1.99-1.92 (m, 2H), 1.87-1.80(m, 2H). Mass (m/z): 581.25 [M+H]⁺.

4-((4-(1-(3,4-dimethoxybenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl)sulfonyl)-N,N-dimethylbutanamide(151)

The titled compound was prepared in a yield of 15% (3 mg, 0.0053 mmol)as a white solid from 140-01(15 mg, 0.035 mmol) and4-bromo-N,N-dimethylbutanamide (21 mg, 0.11 mmol) according to theprocedure for 140. ¹HNMR (400 MHz, CDCl₃) δ 8.96 (d, J=2.4 Hz, 1H), 7.99(dd, J=2.8, 9.6 Hz, 1H), 7.62 (s, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.99 (dd,J=2.0, 8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.78 (d, J=9.6 Hz, 1H), 5.28(s, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.75 (t, J=7.2 Hz, 2H), 3.03 (s,3H), 2.93 (s, 3H), 2.62 (t, J=6.8 Hz, 2H), 2.30-2.24 (m, 2H). Mass(m/z). 569.24 [M+H]⁺.

1-(3,4-dimethoxybenzyl)-5-(2-((4-oxo-4-(pyrrolidin-1-yl)butyl)sulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(152)

The titled compound was prepared in a yield of 28% (9 mg, 0.015 mmol) asa colorless oil from 140-01(23 mg, 0.054 mmol) and4-bromo-1-(pyrrolidin-1-yl)butan-1-one (36 mg, 0.16 mmol) according tothe procedure for 140. ¹HNMR (400 MHz, CDCl₃) δ 9.07 (d, J=2.8 Hz, 1H),7.96 (dd, J=2.8, 9.6 Hz, 1H), 7.82 (s, 1H), 7.04 (d, J=2.0 Hz, 1H), 7.01(dd, J=2.0, 8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.72 (d, J=9.6 Hz, 1H),5.29 (s, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.81-3.77 (m, 2H), 3.40 (t,J=6.8 Hz, 4H), 2.54 (t, J=6.4 Hz, 2H), 2.29-2.22 (m, 2H), 1.96 (q, J=6.4Hz, 2H), 1.87-1.82 (m, 2H). Mass (m/z): 595.24 [M+H]⁺.

1-(3,4-dimethoxybenzyl)-5-(2-((3-oxo-3-(piperidin-1-yl)propyl)sulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(153) and1-(2-chloro-4,5-dimethoxybenzyl)-5-(2-((3-oxo-3-(piperidin-1-yl)propyl)sulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(154)

The titled compound 153 (8 mg, 20% yield) and 154 (3 mg, 7% yield) wasprepared as two white solids from 140-01(28 mg, 0.066 mmol) and3-bromo-1-(piperidin-1-yl)propan-1-one (44 mg, 0.20 mmol) according tothe procedure for 140. 153: ¹HNMR (400 MHz, CDCl₃) δ 8.75 (d, J=2.4 Hz,1H), 8.02 (dd, J=2.4, 9.6 Hz, 1H), 7.82 (s, 1H), 6.98 (m, 1H), 6.97-6.95(m, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.82 (d, J=9.6 Hz, 1H), 5.23 (s, 2H),3.97 (t, J=7.2 Hz, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.51 (t, J=5.6 Hz,2H), 3.44-3.41 (m, 2H), 3.03 (t, J=7.6 Hz, 2H), 1.66-1.53 (m, 6H). Mass(m/z): 595.28 [M+H]⁺: 154: ¹HNMR (400 MHz, CDCl₃) δ 8.87 (d, J=2.4 Hz,1H), 8.07 (dd, J=2.4, 9.2 Hz, 1H), 7.82 (s, 1H), 7.11 (s, 1H), 6.91 (s,1H), 6.80 (d, J=9.6 Hz, 1H), 5.33 (s, 2H), 3.95 (t, J=7.2 Hz, 2H), 3.87(s, 3H), 3.86 (s, 3H), 3.52 (t, J=5.6 Hz, 2H), 3.42 (t, J=5.2 Hz, 2H),3.03 (t, J=7.6 Hz, 2H), 1.68-1.63 (m, 2H), 1.62-1.59 (m, 2H), 1.56-1.51(m, 2H). Mass (m/z): 629.24 [M+H]⁺.

1-(3,4-dimethoxybenzyl)-5-(2-((4-oxo-4-(piperidin-1-yl)butyl)sulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(155)

The titled compound was prepared in a yield of 75% (27 mg, 0.044 mmol)as a white solid from 140-01(25 mg, 0.059 mmol) and4-bromo-1-(piperidin-1-yl)butan-1-one (41 mg, 0.18 mmol) according tothe procedure for 140. HNMR (400 MHz, CDCl₃) δ 8.99 (d, J=2.8 Hz, 1H),7.98 (dd, J=2.8, 9.6 Hz, 1H), 7.83 (s, 1H), 7.01 (d, J=2.0 Hz, 1H), 6.97(dd, J=2.0, 8.0 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.72 (d, J=9.6 Hz, 1H),5.25 (s, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.77-3.73 (m, 2H), 3.48 (m,2H), 3.37 (m, 2H), 2.58 (t, J=6.8 Hz, 2H), 2.28-2.21 (m, 2H), 1.65-1.59(m, 2H), 1.54 (m, 2H), 1.47 (m, 2H). Mass (m/z). 609.27 [M+H]⁺.

1-(3,4-dimethoxybenzyl)-5-(2-((4-morpholino-4-oxobutyl)sulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(156) and1-(2-chloro-4,5-dimethoxybenzyl)-5-(2-((4-morpholino-4-oxobutyl)sulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(157)

The titled compound 156 (3 mg, 100% yield) and 157 (11 mg, 34% yield)was prepared as two white solids from 140-01(21 mg, 0.05 mmol) and4-bromo-1-morpholinobutan-1-one (35 mg, 0.15 mmol) according to theprocedure for 140. 156: ¹HNMR (400 MHz, CDCl₃) δ 8.87 (d, J=2.4 Hz, 1H),8.12 (dd, J=2.8, 9.6 Hz, 1H), 7.83 (s, 1H), 6.99 (d, J=2.0 Hz, 1H), 6.97(dd, J=2.0, 8.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.81 (d, J=9.6 Hz, 1H),5.25 (s, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.76-3.72 (m, 2H), 3.70-3.68(m, 2H), 3.66-3.63 (m, 2H), 3.60-3.57 (m, 2H), 3.49-3.47 (m, 2H), 2.64(t, J=6.8 Hz, 2H), 2.29 (q, J=6.8 Hz, 2H). Mass (m/z): 611.26 [M+H]⁺;

157: ¹HNMR (400 MHz, CDCl₃) δ 8.93 (d, J=2.4 Hz, 1H), 8.05 (dd, J=2.8,10.0 Hz, 1H), 7.82 (s, 1H), 7.09 (s, 1H), 6.90 (s, 1H), 6.77 (d, J=10.0Hz, 1H), 5.33 (s, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.73 (t, J=7.2 Hz,2H), 3.69-3.65 (m, 4H), 3.60-3.58 (m, 2H), 3.49-3.46 (m, 2H), 3.63 (t,J=6.8 Hz, 2H), 2.29 (q, J=6.8 Hz, 2H). Mass (m/z): 645.18 [M+H]⁺.

4-((4-(1-(3,4-dimethoxybenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl)sulfonyl)butanamide(158) and4-((4-(1-(3,4-dimethoxybenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl)sulfinyl)butanamide159

The titled compound 158 (9 mg, 35% yield) and 159 (7 mg, 28% yield) wasprepared as two white solids from 140-01(20 mg, 0.047 mmol) and4-bromobutanamide (24 mg, 0.14 mmol) according to the procedure for 140.

158: ¹HNMR (400 MHz, CDCl₃) δ 8.79 (d, J=2.4 Hz, 1H), 7.97 (dd, J=2.8,10.0 Hz, 1H), 7.82 (s, 1H), 6.98 (m, 1H), 6.96-6.94 (m, 1H), 6.86 (d,J=8.4 Hz, 1H), 6.74 (d, J=10.0 Hz, 1H), 5.63 (br, 1H), 5.54 (br, 1H),5.23 (s, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.70 (t, J=7.2 Hz, 2H), 2.50(t, J=6.4 Hz, 2H), 2.29-2.21 (m, 2H); Mass (m/z): 541.27 [M+H]⁺.

159: ¹HNMR (400 MHz, CDCl₃) δ 8.69 (s, 1H), 7.70 (s, 1H), 6.97 (m, 1H),6.95 (m, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.74 (d, J=9.6 Hz, 1H), 5.73 (br,1H), 5.55 (br, 1H), 5.20 (s, 2H), 5.87 (s, 3H), 5.86 (s, 3H), 3.33-3.20(m, 2H), 2.46 (t, J=6.8 Hz, 2H), 2.11-2.07 (m, 2H); Mass (m/z): 525.24[M+H]⁺.

5-(6-(difluoromethyl)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(160)

Step 1. The titled compound 160-01 was prepared in a yield of 80% (460mg) as a white solid from ethyl 4,4-difluoro-3-oxobutanoate (495 mg, 3mmol) and methyl carbamimidothioate (1.12 g, 6 mmol) according to theprocedure for 43-01. ¹H NMR (400 Hz, acetone-d₆) δ 6.83 (s, 0.66H), 6.69(s, 1H), 6.56 (s, 0.58H), 6.34 (s. 1H), 2.52 (s, 3H); Mass (m/z): 193.5[M+H]⁺.

Step 2. The titled compound 160-02 was prepared in a yield of 90% (492mg) as a white solid from 160-01 (500 mg, 2.6 mmol) and phosphorusoxychloride (4 ml) according to the procedure for 49-01. ¹H NMR (400 Hz,CDCl₃) δ 7.25 (s, 1H), 6.59 (s, 0.24H), 6.44 (s, 0.46H), 6.29 (s,0.24H), 2.58 (s, 3H); Mass (m/z): 211.2 [M+H]⁺.

Step 3. The titled compound 160-03 was prepared in a yield of 66% (20mg) as a white solid from 160-02 (27 mg, 0.13 mmol) according to theprocedure for 99-01; Mass (m/z): 420.4 [M+H]⁺.

Step 4. The titled compound 160 was prepared in a yield of 50% (10.7 mg)as a white solid from 160-03 (20 mg, 0.048 mmol) and Oxone (146 mg, 0.24mmol) according to the procedure for 49. ¹H NMR (400 Hz, CDCl₃) δ 8.61(d, J=2.4 Hz, 1H), 7.99 (dd, J=2.4, 9.6 Hz, 1H), 7.81 (s, 1H), 6.94 (d,J=2.0 Hz, 1H), 6.92 (dd, J=2.0, 8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H),6.74 (d, J=9.6 Hz, 1H), 6.62 (s, 0.6H), 6.48 (s, 0.4H), 5.29 (s, 2H),3.86 (s, 6H), 3.35 (s, 3H); Mass (m/z): 452.5 [M+H]⁺.

5-(6-(fluoromethyl)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(161)

Step 1: The titled compound 161-01 was prepared in a yield of 86% (693mg) as a white solid from ethyl 4-fluoro-3-oxobutanoate (677 mg, 4.6mmol) and methyl carbamimidothioate (1.7 g, 9.3 mmol) according to theprocedure for 43-01; Mass (m/z): 175.1 [M+H]⁺.

Step 2. The titled compound 161-02 was prepared in a yield of 76% (150mg) as a white solid from 161-01 (180 mg, 1.03 mmol) and phosphorusoxychloride (2 ml) according to the procedure for 49-01. ¹H NMR (400 Hz,CDCl₃) δ 7.16 (s. 1H), 5.42 (s. 1H), 5.30 (s, 1H), 2.56 (s, 3H).

Step 3. The titled compound 161-03 was prepared in a yield of 14% (12mg) as a white solid from 161-02 (80 mg, 0.22 mmol) according to theprocedure for 99-01. ¹H NMR: (400 Mz, CDCl₃): δ 8.37 (d, J=2.4 Hz, 1H),7.96 (dd, J=2.4, 9.6 Hz, 1H), 7.40 (s, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.88(dd, J=2.0, 8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.70 (d, J=9.6 Hz, 1H),5.42 (s, 1H), 5.31 (s, 1H), 5.16 (s, 2H), 3.86 (s, 6H), 2.5 (s, 3H);Mass (m/z): 402.5 [M+H]⁺.

Step 4. The titled compound 161 was prepared in a yield of 36% (4.7 mg)as a white solid from 161-03 (12 mg, 0.031 mmol) and Oxone (48 mg, 0.078mmol) according to the procedure for 49. ¹H NMR: (400 Mz, CDCl3): δ 8.54(d, J=2.4 Hz, 1H), 7.97 (dd, J=2.4, 9.6 Hz, 1H), 7.71 (s, 1H), 6.93 (d,J=2.0 Hz, 1H), 6.90 (dd, J=2.0, 8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H),6.71 (d, J=9.6 Hz, 1H), 5.59 (s, 1H), 5.47 (s, 1H), 5.17 (s, 2H), 3.86(s, 6H), 3.30 (s, 3H); Mass (m/z): 434.5 [M+H]⁺.

5-(5-chloro-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(162)

Step 1. Preparation of5-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-ol (162-01): Asolution of 2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-ol (210 mg, 1mmol) in AcOH (3 mL) was added Ac₂O (0.2 ml), FeCl₃(40 mg) andSO₂Cl₂(150 mg) Then refluxed at 110° C. for 6 h. The reaction mixturewas cooled to room temperature, and solvent was removed in vacuo. Theresidue was extracted by DCM and icy H₂O 3 times. The organic layer wascombined, washed with brine, dried over Na₂SO₄ and concentrated to give110 mg of 5-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-ol(162-01) as a light yellow oid (45%). Mass (m/z): 245.5 [M+H]⁺.

Step 2. The titled compound 162-02 was prepared in a yield of 27% (12mg) as a white solid from 162-01 (42 mg, 0.172 mmol) and phosphorusoxychloride (2 ml) according to the procedure for 49-01.

Step 3. The titled compound 162-03 was prepared in a yield of 42% (15mg) as a white solid from 162-02 (20 mg, 0.076 mmol) according to theprocedure for 99-01. Mass (m/z): 272.4 [M+H]⁺.

Step 4. The titled compound 162 was prepared in a yield of 40% (6.4 mg)as a white solid from 162-03 (15 mg, 0.032 mmol) and Oxone (100 mg,0.016 mmol) according to the procedure for 67. ¹H NMR: (400 Mz, CDCl₃):δ 8.41 (d, J=2.4 Hz, 1H), 8.10 (dd, J=2.4, 9.6 Hz, 1H), 6.93 (d, J=2.0Hz, 1H), 6.90 (dd, J=2.0, 8.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.70 (d,J=9.6 Hz, 1H), 5.16 (s, 2H)), 3.87 (s, 6H), 3.38 (s, 3H). Mass (m/z):504.3 [M+H]⁺.

5-(6-acetyl-2-(methylsulfonyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(163)

Step 1. The titled compound 163-01 was prepared according to theprocedure for 43-01. Mass (m/z): 187.1 [M+H]⁺.

Step 2. The titled compound 163-02 was prepared from 163-01(19.6 mg, 0.1mmol) according to the procedure for for 49-01.

Step 3. To a mixture of 6-chloro-2-(methylthio)pyrimidine-4-carbonylchloride (163-02) and N,O-dimethylhydroxylamine hydrochloride in CH₂C₂at 0° C. was slowly added EtN₃. The reaction mixture was stirred at 0°C. for 4 h. The reaction mixture was quenched with NH₄Cl, The residuewas extracted by CH₂Cl₂/H₂O 3 times. The organic layer was washed withbrine, dried over Na₂SO₄ and further purified by silica gel columnchromatography (PE/EA=5/l) to give 50 mg of6-chloro-N-(methoxymethyl)-N-methyl-2-(methylthio)pyrimidine-4-carboxamide(163-03) as a light yellow oil (15% for three steps). ¹H NMR: (400 Mz,CDCl₃): δ 7.14 (s, 1H), 3.74 (s, 3H), 3.34 (s, 3H), 2.59 (s, 3H). Mass(m/z): 248.0 [M+H]⁺.

Step 4. Methylmagnesium bromide was slowly added to a solution of 163-03(42 mg) in dry THF under Ar at 0° C., the reaction mixture was stirredat 0° C. for 2 h. The reaction mixture was quenched with NH₄Cl, Theresidue was extracted by EtOAc/H₂O 3 times. The organic layer was washedwith brine, dried over Na₂SO₄ and further purified by silica gel columnchromatography (PE/EA=5/1) to give 24 mg of1-(6-chloro-2-(methylthio)pyrimidin-4-yl)ethanone (163-04) as a lightyellow oil (70%). ¹H NMR: (400 Mz, CDCl₃): δ 7.52 (s, 1H), 2.68 (s, 3H),2.63 (s, 3H), 2.59 (s, 3H). Mass (m/z): 203.0 [M+H]⁺.

Step 5. The titled compound 163-05 was prepared in a yield of 40% (10mg) as a white solid from 163-04 (19.6 mg, 0.1 mmol) according to theprocedure for 99-01. Mass (m/z): 412.2 [M+H]⁺. Step 6. The titledcompound 163 was prepared in a yield of 45% as a white solid from 200-05(10 mg, 0.024 mmol) and Oxone (45 mg, 0.073 mmol) according to theprocedure for 67.

¹H NMR: (400 Mz, CDCl3): δ 8.56 (d, J=2.8 Hz, 1H), 8.11 (s, 1H), 8.04(dd, J=2.4, 9.6 Hz, 1H), 6.95 (d, J=2.0 Hz, 1H), 6.92 (dd, J=2.0, 8.0Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.74 (d, J=9.6 Hz, 1H), 5.30 (s, 2H),3.87 (s, 3H), 3.86 (s, 3H), 3.39 (s, 3H), 2.76 (s, 3H). Mass (m/z):444.2 [M+H]⁺.

5-(6-(1,1-difluoroethyl)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(164)

Step 1. A solution of 1-(6-chloro-2-(methylthio)pyrimidin-4-yl)ethanone(163-04) in CH₂Cl₂ was slowly added to cooled (0° C.) solution of DASTin CH₂Cl₂. The reaction mixture was warmed up to it and stirred at rtfor 23 h. The reaction mixture was quenched with NaHCO₃ (sat. soln), Theresidue was extracted by CH₂Cl₂/H₂O 3 times. The organic layer waswashed with brine, dried over Na₂SO₄ and further purified by silica gelcolumn chromatography (PE/EA=5/1) to give 50 mg of4-chloro-6-(1,1-difluoroethyl)-2-(methylthio)pyrimidine (164-01) as alight yellow oil (43%). ¹H NMR: (400 Mz, CDCl₃): δ 7.28 (s, 1H), 2.58(s, 3H), 1.96 (m, 3H), Mass (m/z): 225.1 [M+H]⁺.

Step 2. The titled compound 164-02 was prepared in a yield of 42% (5 mg)as a white solid from 164-01 (6 mg, 0.027 mmol) according to theprocedure for 99-01. Mass (m/z): 434.2 [M+H]⁺.

Step 3. The titled compound 164 was prepared in a yield of 60% as awhite solid from 164-02 (5.4 mg, 0.013 mmol) and Oxone (23 mg, 0.037mmol) according to the procedure for 67. H NMR: (400 Mz, CDCl3): δ 8.58(s, 1H), 7.97 (d, 9.6 Hz, 1H), 7.73 (s, 1H), 6.93 (d, J=2.0 Hz, 1H),6.92 (dd, J=2.0, 8.0 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.72 (d, J=9.6 Hz,1H), 5.18 (s, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.35 (s, 3H), 2.18 (m,3H). Mass (m/z): 466.2 [M+H]⁺.

5-(6-(difluoromethyl)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)-3-fluoropyridin-2(1H)-one(165)

Step 1. A mixture of 5-bromo-3-fluoro-2-methoxypyridine (206 mg, 1.0mmol), bis(pinacolato)diboron (508 mg, 2.0 mmol), Pd(PPh₃)Cl₂(70.1 mg,0.05 mmol), KOAc (294 mg, 3.0 mmol) and 1,4-dioxane (4 ml) was heated at80° C. Under Ar for 4 h. The reaction mixture was then cooled and pouredover ice. The residue was extracted by EtOAc 3 times. The organic layerwas washed with brine, dried over Na₂SO₄ and further purified by silicagel column chromatography (PE/EA=9/1) to give 228 mg of 165-01 as alight yellow oil (90%). Mass (m/z): 254.2 [M+H]⁺.

Step 2. The titled compound 165-02 was prepared in a yield of 72% (130mg) as a white solid from 160-02 (125 mg, 0.6 mmol) according to theprocedure for 99-01. Mass (m/z): 302.1 [M+H]⁺.

Step 3. A solution of (165-02) in EtOH was slowly added HBr. The mixturesolution was heated at 95° C. for 3.5 h. The reaction mixture was cooledto room temperature, and solvent was removed in vacuo. The residue wasextracted by EtOAc 3 times. The organic layer was combined, washed withbrine, dried over Na₂SO₄ and further purified by recrystallization by(PE/EA=1/9) to give 99 mg of3-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(165-03) as a light yellow solid (80%). ¹H NMR: (400 Mz, DMSO-d6): δ12.83 (s, 1H), 8.42 (s, 3H), 8.22 (dd, J=2.0, 12.0 Hz, 1H), 7.95 (s,1H), 7.02 (s, 0.2H), 6.89 (s, 0.4H), 6.75 (s, 0.3H), 2.60 (s, 3H). Mass(m/z): 288.1 [M+H]⁺.

Step 4. To a mixture of5-(6-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)-3-fluoropyridin-2(1H)-one(50 mg, 0.17 mmol), 4-(bromomethyl)-1,2-dimethoxybenzene (60 mg, 0.26mmol) in DMF (3 ml) was slowly added NaH (10 mg, 0.26 mmol) at 0° C.Then warm to RT for 6 h. The reaction mixture was then cooled and pouredover ice. The residue was extracted by EtOAc 3 times. The organic layerwas washed with brine, dried over Na₂SO₄ and further purified by silicagel column chromatography (PE/EA=2/1) to give 60 mg of5-(6-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)-3-fluoropyridin-2(1H)-one(165-04) as a light yellow oil (78%). ¹H NMR: (400 Mz, CDCl3): δ 8.19(s, 1H), 7.76 (dd, 2.0, 10.0 Hz, JH), 6.92-6.81 (m, 4H), 6.48 (s, 0.2H),6.40 (s, 0.4H), 6.25 (s, 0.3H), 5.18 (s, 2H), 3.83 (s, 3H), 3.81 (s,3H), 2.51 (s, 3H). Mass (m/z): 438.2 [M+H]⁺.

Step 4. The titled compound 165 was prepared in a yield of 66% as awhite solid from 165-04 (59 mg, 0.14 mmol) and Oxone (250 mg, 0.41 mmol)according to the procedure for 67. H NMR: (400 Mz, CDCl3): δ 8.44 (s,1H), 7.79-7.78 (m, 2H), 6.95-6.93 (m, 2H), 6.85 (d, J=8.0 Hz, 1H), 6.78(s, 0.2H), 6.62 (s, 0.4H), 6.50 (s, 0.3H), 5.23 (s, 2H), 3.87 (s, 3H),3.86 (s, 3H), 3.36 (s, 3H). Mass (m/z): 470.1 [M+H]⁺.

1-(3,4-dimethoxybenzyl)-5-(6-methyl-2-((2,2,2-trifluoroethyl)sulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(166)

Step 1. The titled compound 166-01 was prepared in a yield of 84% (540mg) as a white solid from 6-methylpyrimidine-2,4-diol (500 mg, 3.97mmol) and phosphorus oxychloride (4 ml) according to the procedure for49-01. Mass (m/z): 164.7 [M+H]⁺.

Step 2. The titled compound 166-02 was prepared in a yield of 80% (188mg) as a white solid from 166-01 (163 mg, 1.0 mmol) according to theprocedure for 99-01. ¹H NMR: (400 Mz, CDCl3): δ 9.27 (d, J=2.4 Hz, 1H),8.66 (dd, J=2.4, 9.2 Hz, 1H), 7.09 (s, 1H), 6.88 (d, J=9.2 Hz, 1H), 4.03(s, 6H), 2.56 (s, 3H). Mass (m/z): 236.1 [M+H]⁺.

Step 3. To a mixture of 166-02 (146 mg, 0.61 mmol), CF₃CH₂SH (1.0 g,) inDMF (3 ml) was slowly added NaH (49 mg, 1.28 mmol) at 0° C. Then warm toRT for 18 h. The reaction mixture was then cooled and poured over ice.The residue was extracted by EtOAc 3 times. The organic layer was washedwith brine, dried over Na₂SO₄ and further purified by silica gel columnchromatography (PE/EA=5/1) to give 38 mg of 166-03 as a light yellow oil(20%). Mass (m/z): 316.2 [M+H]⁺.

Step 4. The titled compound 166-04 was prepared as a white solid from166-03 (3 mg, 0.013 mmol) according to the procedure for 165-03. Mass(m/z): 303.1 [M+H]⁺.

Step 5. The titled compound 166-05 was prepared as a white solid from166-04 (0.013 mmol) according to the procedure for 165-04. Mass (m/z):452.2 [M+H]⁺.

Step 6. The titled compound 166 was prepared in a yield of 32% (for 3steps) as a white solid from 166-05 (0.013 mmol) and Oxone (20 mg, 0.032mmol) according to the procedure for 67. H NMR: (400 Mz, CDCl₃): δ 8.60(d, 9.6 Hz, 1H), 8.33 (dd, J=2.0, 8.0 Hz, 1H), 7.63 (s, 1H), 7.00-6.86(m, 2H), 6.85 (d, J=8.4 Hz, 1H), 6.71 (d, J=9.2 Hz, 1H), 5.19 (s, 2H),3.83 (s, 3H), 3.81 (s, 3H), 2.70 (s, 1H), 2.22-2.16 (m, 2H). Mass (m/z):484.2 [M+H]⁺.

5-(6-(difluoromethyl)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(3-fluoro-4-methoxybenzyl)pyridin-2(11H)-one(167) and5-(6-(difluoromethyl)-2-(methylsulfinyl)pyrimidin-4-yl)-1-(3-fluoro-4-methoxybenzyl)pyridin-2(1H)-one(168)

The titled compound 167 (12 mg, 25% yield) and 168 (6 mg, 13% yield) wasprepared as two colorless oil from5-(6-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (30mg, 0.11 mmol) and 4-(bromomethyl)-2-fluoro-1-methoxybenzene (28 mg,0.13 mmol) according to the procedure for 100. 167: ¹HNMR (400 MHz,CDCl₃) δ 8.60 (d, J=2.8 Hz, 1H), 8.01 (dd, J=2.8, 9.6 Hz, 1H), 7.84 (s,1H), 7.12 (t, J=2.0 Hz, 1H), 7.10 (m, 1H), 6.95 (t, J=8.4 Hz, 1H), 6.75(d, J=9.6 Hz, 1H), 6.62 (t, J=54.4 Hz, 1H), 5.17 (s, 2H), 3.87 (s, 3H),3.38 (s, 3H). Mass (m/z): 440.18[M+H]⁺. 168: ¹HNMR (400 MHz, CDCl₃) δ8.60 (d, J=2.4 Hz, 1H), 8.03 (dd, J=2.8, 9.6 Hz, 1H), 7.73 (s, 1H), 7.12(m, 1H), 7.10 (m, 1H), 6.94 (t, J=8.0 Hz, 1H), 6.75 (d, J=9.6 Hz, 1H),6.64 (t, J=54.4 Hz, 1H) 5.18 (d, J=3.2 Hz, 2H), 3.87 (s, 3H), 2.99 (s,3H). Mass (m/z): 424.18 [M+H]⁺.

5-(6-(difluoromethyl)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(4-methoxy-3-(trifluoromethyl)benzyl)pyridin-2(1H)-one(169) and5-(6-(difluoromethyl)-2-(methylsulfinyl)pyrimidin-4-yl)-1-(4-methoxy-3-(trifluoromethyl)benzyl)pyridin-2(1H)-one(170)

The titled compound 169 (13 mg, 25% yield) and 170 (10 mg, 19% yield)was prepared as two colorless oil from5-(6-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (30mg, 0.11 mmol) and 4-(bromomethyl)-1-methoxy-2-(trifluoromethyl)benzene(46 mg, 0.17 mmol) according to the procedure for 100. 169: ¹HNMR (400MHz, CDCl₃) J 8.63 (d, J=2.4 Hz, 1H), 8.02 (dd, J=2.8, 9.6 Hz, 1H), 7.86(s, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.56 (dd, J=2.4, 8.4 Hz, 1H), 7.01 (d,J=8.8 Hz, 1H), 6.74 (d, J=9.6 Hz, 1H), 6.62 (t, J=54.4 Hz, 1H), 5.21 (s,2H), 3.89 (s, 3H), 3.37 (s, 3H). Mass (m/z): 490.21 [M+H]⁺. 170: ¹HNMR(400 MHz, CDCl₃) δ 8.67 (d, J=2.4 Hz, 1H), 8.03 (dd, J=2.8, 9.6 Hz, 1H),7.75 (s, 1H), 7.58-7.54 (m, 2H), 7.00 (d, J=8.4 Hz, 1H), 6.75 (d, J=9.6Hz, 1H), 6.63 (t, J=54.4 Hz, 1H), 5.22 (d, J=7.6 Hz, 2H), 3.89 (s, 3H),2.99 (s, 3H). Mass (m/z): 474.18 [M+H]⁺.

5-(6-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)-1-(3-fluoro-4,5-dimethoxybenzyl)pyridin-2(1H)-one(171)

The titled compound 171 (12 mg, 25% yield) was prepared as white solidfrom5-(6-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (30mg, 0.11 mmol) and 5-(chloromethyl)-1-fluoro-2,3-dimethoxybenzene (30mg, 0.15 mmol) according to the procedure for 100. ¹HNMR (400 MHz,CDCl₃) δ 8.40 (d, J=2.4 Hz, 1H), 8.00 (dd, 2.8, 9.6 Hz, 1H), 7.34 (s,1H), 6.73 (d, J=3.6 Hz, 1H), 6.70-6.67 (m, 1H), 6.46 (t, J=54.4 Hz, 1H),5.14 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 2.57 (s, 3H). Mass (m/z):438.26 [M+H]⁺.

5-(6-(difluoromethyl)-2-((3-methoxybenzyl)sulfonyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(172) and5-(6-(difluoromethyl)-2-((3-methoxybenzyl)sulfinyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(173)

Step 1: The titled compound 172-1 was prepared as yellow oil fromcompound 160 (100 mg, 0.22 mmol) according to the procedure for 140-01,Mass (m/z): 406.21 [M+H]⁺.

Step 2: The titled compound 172 (13 mg), and 173 (11 mg, 25% yield) wereprepared as two white solids from 172-1 (24 mg, 0.059 mmol) and1-(bromomethyl)-3-methoxybenzene (18 mg, 0.089 mmol) according to theprocedure for 140. 172: ¹HNMR (400 MHz, CDCl₃) δ 8.59 (d, J=2.4 Hz, 1H),7.96 (dd, J=2.4, 9.6 Hz, 1H), 7.76 (s, 1H), 7.19 (t, J=8.4 Hz, 1H), 6.94(t, J=2.0 Hz, 1H), 6.91-6.88 (m, 2H), 6.86-6.81 (m, 2H), 6.74 (d, J=9.6Hz, 1H), 6.63 (t, J=54.4 Hz, 1H), 5.18 (s, 2H), 4.74 (s, 2H), 3.86 (s,3H), 3.82 (s, 3H), 3.74 (s, 3H). Mass (m/z): 558.28 [M+H]⁺.173: ¹HNMR(400 MHz, CDCl₃) δ 8.50 (d, J=2.4 Hz, 1H), 7.97 (dd, J=2.4, 9.6 Hz, 1H),7.66 (s, 1H), 7.16 (t, J=8.0 Hz, 1H), 6.96 (m, 1H), 6.93 (dd, J=1.6, 8.4Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.81 (dd, J=2.4, 8.4 Hz, 1H), 6.71 (m,2H), 6.60 (t, J=54.4 Hz, 1H), 5.18 (s, 2H), 4.37 (d, J=12.8 Hz, 1H),4.26 (d, J=12.8 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.73 (s, 3H). Mass(m/z): 542.26 [M+H]⁺.

5-(6-(difluoromethyl)-2-((3-methoxyphenyl)sulfonyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(174) and5-(6-(difluoromethyl)-2-((3-methoxyphenyl)sulfinyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(175)

Step 1: At 0° C., to a stirred solution of 3-methoxybenzenethiol (14 mg,0.099 mmol) in DMF (5 mL) was added NaH (5 mg, 0.13 mmol), which wasstirred for 30 min, then compound 160 (30 mg, 0.066 mmol) was added tothe above mixture and stirred for another 2 h, sat NH4Cl was added toquench the reaction, and extracted by EA for 3 times, concentrated theorganic layer, and purified by flash chromatography with EA/PE (1/2), 30mg colorless oil of 174-1 was obtained with a yield 89%. ¹HNMR (400 MHz,CDCl₃) δ 8.17 (d, J=2.8 Hz, 1H), 7.79 (dd, J=2.8, 9.6 Hz, 1H), 7.36 (t,J=8.0 Hz, 1H), 7.31 (s, 1H), 7.23-7.21 (m, 2H), 7.03-7.00 (m, 1H), 6.93(d, J=2.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.78 (dd, J=2.0, 8.4 Hz, 1H),6.63 (d, J=9.6 Hz, 1H), 6.40 (t, J=54.4 Hz, 1H), 5.02 (s, 2H), 3.86 (s,3H), 3.84 (s, 3H), 3.80 (s, 3H). Mass (m/z): 512.22 [M+H]⁺.

Step 2: The titled compound 174 (18 mg, 56% yield) and 175 (13 mg, 42%yield) was prepared as two white solids according to the procedure for140.174: ¹HNMR (400 MHz, CDCl₃) δ 8.48 (d, J=2.8 Hz, 1H), 7.92 (dd,J=2.4, 9.6 Hz, 1H), 7.71 (s, 1H), 7.68-7.65 (m, 1H), 7.60 (dd, J=1.6,2.4 Hz, 1H), 7.54-7.52 (m, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.22-7.19 (m,1H), 6.95 (d, J=2.0 Hz, 1H), 6.91 (dd, J=2.0, 8.0 Hz, 1H), 6.87 (d,J=8.0 Hz, 1H), 6.58 (t, J=54.4 Hz, 1H), 5.16 (s, 2H), 3.88 (s, 6H), 3.86(s, 3H). Mass (m/z): 544.24 [M+H]⁺. 175: ¹HNMR (400 MHz, CDCl₃) δ 8.52(d, J=2.4 Hz, 1H), 7.97 (dd, J=2.4, 9.6 Hz, 1H), 7.61 (s, 1H), 7.42 (m,1H), 7.35-7.32 (m, 2H), 6.99-6.93 (m, 3H), 6.88 (d, J=8.8 Hz, 1H), 6.73(d, J=9.6 Hz, 1H), 6.61 (t, J=54.4 Hz, 1H), 5.20 (d, J=6.8 Hz, 2H), 3.88(s, 6H), 3.81 (s, 3H). Mass (m/z): 528.24 [M+H]⁺.

4-((4-(difluoromethyl)-6-(1-(3,4-dimethoxybenzyl)-6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-2-yl)sulfonyl)-N-methylbutanamide(176) and4-((4-(difluoromethyl)-6-(1-(3,4-dimethoxybenzyl)-6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-2-yl)sulfinyl)-N-methylbutanamide(177)

The titled compound 176 (6 mg, 14% yield) and 177 (3 mg, 7% yield) wasprepared as two white solids from 172-1 (33 mg, 0.081 mmol) and4-bromo-N-methylbutanamide (29 mg, 0.16 mmol) according to the procedurefor 140. 176: ¹HNMR (400 MHz, CDCl3) δ 8.85 (d, J=2.4 Hz, 1H), 7.98 (dd,J=2.4, 9.6 Hz, 1H), 7.81 (s, 1H), 7.02 (d, J=2.0 Hz, 1H), 7.00 (dd,J=2.0, 8.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.75 (d, J=9.6 Hz, 1H), 6.65(t, J=54.4 Hz, 1H), 5.59 (br, 1H), 5.28 (s, 2H), 3.88 (s, 3H), 3.87 (s,3H), 3.68 (t, J=7.6 Hz, 2H), 2.80 (d, J=4.8 Hz, 3H), 2.44 (t, J=6.8 Hz,2H), 2.29-2.22 (m, 2H). Mass (m/z): 537.38 [M+H]⁺. 177: ¹HNMR (400 MHz,CDCl₃) δ 8.64 (d, J=2.4 Hz, 1H), 8.01 (dd, J=2.8, 9.6 Hz, 1H), 7.70 (s,1H), 6.99 (m, 1H), 6.96 (dd, J=2.0, 8.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H),6.76 (d, J=9.6 Hz, 1H), 6.64 (t, J=54.4 Hz, 1H), 5.78 (br, 1H), 5.22 (s,2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.29-3.21 (m, 2H), 2.79 (d, J=4.8 Hz,3H), 2.41 (t, J=6.8 Hz, 2H), 2.12-2.05 (m, 2H). Mass (m/z): 521.35[M+H]⁺.

3-((4-(difluoromethyl)-6-(1-(3,4-dimethoxybenzyl)-6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-2-yl)sulfonyl)-N-methylpropane-1-sulfonamide(178) and3-((4-(difluoromethyl)-6-(1-(3,4-dimethoxybenzyl)-6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-2-yl)sulfinyl)-N-methylpropane-1-sulfonamide(179)

The titled compound 178 (7 mg, 16% yield) and 179 (4 mg, 100% yield) wasprepared as two white solids from 172-1 (30 mg, 0.075 mmol) and3-chloro-N-methylpropane-1-sulfonamide (27 mg, 0.16 mmol) according tothe procedure for 140. 178: ¹HNMR (400 MHz, CDCl₃) δ 8.69 (d, J=2.4 Hz,1H), 7.98 (dd, J=2.8, 9.6 Hz, 1H), 7.83 (s, 1H), 6.98-6.96 (m, 2H), 6.87(d, J=8.0 Hz, 1H), 6.76 (d, J=10.0 Hz, 1H), 6.65 (t, J=55.4 Hz, 1H),5.22 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.82 (t, J=7.2 Hz, 2H), 3.26(t, J=6.8 Hz, 2H), 2.83 (d, J=5.2 Hz, 3H), 2.47-2.40 (m, 2H). Mass(m/z): 573.40 [M+H]⁺. 179: ¹HNMR (400 MHz, CDCl₃) δ 8.63 (d, J=2.4 Hz,1H), 8.00 (dd, J=2.4, 9.6 Hz, 1H), 7.72 (s, 1H), 6.98-6.95 (m, 2H), 6.87(d, J=8.0 Hz, 1H), 6.77 (d, J=10.0 Hz, 1H), 6.65 (t, J=55.4 Hz, 1H),5.21 (s, 2H), 4.39 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.48-3.43 (m,1H), 3.40-3.33 (m, 1H), 3.20 (t, J=7.2 Hz, 2H), 2.80 (d, J=5.2 Hz, 3H),2.50-2.43 (m, 1H), 2.25-2.16 (m, 1H). Mass (m/z): 557.40 [M+H]⁺.

5-(2-((3-aminophenyl)sulfonyl)-6-(difluoromethyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(180) and5-(2-((3-aminophenyl)sulfinyl)-6-(difluoromethyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(181)

Step 1: The titled compound 180-1 (92 mg, 56% yield) was prepared asyellow syrup from 160(100 mg, 0.22 mmol) and 3-aminobenzenethiol (41 mg,0.33 mmol) according to the procedure for 174-1. ¹HNMR (400 MHz, CDCl₃)δ 8.20 (d, J=2.8 Hz, 1H), 7.80 (dd, J=2.4, 9.6 Hz, 1H), 7.31 (m, 1H),7.24 (d, J=8.0 Hz, 1H), 7.04-6.99 (m, 2H), 6.93 (s, 1H), 6.68-6.79 (m,2H), 6.63 (d, J=9.6 Hz, 1H), 6.41 (t, J=55.4 Hz, 1H), 5.05 (s, 2H), 3.86(s, 3H), 3.85 (s, 3H). Mass (m/z). 497.49 [M+H]⁺.

Step 2: a solution of amine 180-1 (90 mg, 0.17 mmol) in dry THE (5 mL)was blanked with Ar, then a solution of (Boc)2O (54 mg, 0.25 mmol) indry THF (2 mL) was added, when the addition was complete, the mixturewas stirred at 60° C. overnight, concentrated the reaction mixture andpurified by flash chromatography (EA/PE=2/1), 56 mg of 180-2 wasobtained, yield: 55%. ¹HNMR (400 MHz, CDCl₃) δ 8.17 (d, J=2.4 Hz, 1H),7.80 (dd, J=2.4, 9.6 Hz, 1H), 7.37-7.28 (m, 3H), 6.91 (d, J=1.6 Hz, 1H),6.81-6.74 (m, 2H), 6.66-6.62 (m, 2H), 6.41 (t, J=55.4 Hz, 1H), 5.04 (s,2H), 3.86 (s, 3H), 3.84 (s, 3H), 1.50 (s, 9H). Mass (m/z): 597.46[M+H]⁺.

Step 3: The titled compound 180-3 and 181-1 was prepared as bothcolorless oil according to the procedure for 67.180-3: Mass (m/z):629.47 [M+H]⁺, 181-1: Mass (m/z): 613.45 [M+H]⁺.

Step 4: compound 183-3 (31 mg, 0.049 mmol) was dissolved in CH₂Cl₂(5mL), then TFA (1 mL) was added, the whole system was stirred for 30 min,concentrated and purified by Prep-HPLC, 9.0 mg white solid of 180 wasobtained, yield: 35%. ¹HNMR (400 MHz, CDCl₃) δ 8.52 (d, J=2.4 Hz, 1H),7.95 (dd, J=2.4, 9.6 Hz, 1H), 7.73 (s, 1H), 7.41 (d, J=7.8 Hz, 1H),7.33-7.29 (m, 2H), 6.95-6.88 (m, 3H), 6.78 (d, J=9.6 Hz, 1H), 6.59 (t,J=55.4 Hz, 1H), 5.18 (s, 2H), 3.88 (s, 6H). Mass (m/z): 529.45 [M+H]⁺.

Step 5: the tile compound 181 (4 mg, 0.0078 mmol, 24% yield) wasprepared from 181-1 (17 mg, 0.032 mmol) according to the procedure for180. ¹HNMR (400 MHz, CDCl₃) δ 8.55 (s, 1H), 7.98 (d, J=9.6 Hz, 1H), 7.62(s, 1H), 7.33-7.23 (m, 4H), 6.97-6.87 (m, 3H), 6.78 (d, J=9.2 Hz, 1H),6.61 (t, J=54.4 Hz, 1H), 5.21 (d, J=8.0 Hz, 2H), 3.87 (s, 6H). Mass(m/z): 513.41 [M+H]⁺.

N-(3-((4-(difluoromethyl)-6-(1-(3,4-dimethoxybenzyl)-6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-2-yl)sulfonyl)phenyl)acetamide(182)

Step 1: to a stirred solution of 180-1 (20 mg, 0.037 mmol) in CH₂C₂(5mL) was added Ac2O (19 mg, 0.19 mmol) and pyridine (29 mg, 0.37 mmol)successively, which was stirred for 5 h, concentrated and purified byflash chromatography (EA/PE=2/1) 17 mg of white solid was obtained,yield: 85%. Mass (m/z): 539.47 [M+H]⁺.

Step 2: The titled compound 182-1 (6 mg, 33% yield) was prepared ascolorless oil according to the procedure for 67. ¹HNMR (400 MHz, CDCl₃)δ 8.61 (s, 1H), 8.15 (m, 1H), 8.02-7.90 (m, 2H), 7.83-7.81 (m, 1H),7.75-7.68 (m, 2H), 7.53 (d, J=8.4 Hz, 1H), 7.01-6.93 (m, 2H), 6.79-6.74(m, 1H), 6.47 (t, J=54.4 Hz, 1H), 5.25 (s, 2H), 3.92 (s, 3H), 3.87 (s,3H), 2.21 (s, 3H). Mass (m/z): 571.41 [M+H]⁺.

4-((4-(difluoromethyl)-6-(1-(3,4-dimethoxybenzyl)-6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-2-yl)sulfonyl)-N-hexylbutanamide(183) and4-((4-(difluoromethyl)-6-(1-(3,4-dimethoxybenzyl)-6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-2-yl)sulfinyl)-N-hexylbutanamide(184)

The titled compound 183 (3 mg, 3% yield) and 184 (1 mg, 1% yield) wasprepared as two white solids from 172-1 (42 mg, 0.17 mmol) and4-bromo-N-hexylbutanamide (45 mg, 0.11 mmol) according to the procedurefor 140. 183: ¹HNMR (400 MHz, CDCl₃) δ 8.88 (d, J=2.4 Hz, 1H), 7.98 (dd,J=2.8, 9.6 Hz, 1H), 7.81 (s, 1H), 7.02 (d, J=2.0 Hz, 1H), 7.00 (dd,J=2.0, 8.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.74 (d, J=9.6 Hz, 1H), 6.64(t, J=54.4 Hz, 1H), 5.56 (t, J=4.4 Hz, 1H), 5.27 (s, 2H), 3.87 (s, 3H),3.86 (s, 3H), 3.68 (t, J=7.2 Hz, 2H), 3.24-3.19 (m, 2H), 3.43 (t, J=6.8Hz, 2H), 2.28-2.21 (m, 2H), 1.50-1.43 (m, 2H), 1.29-1.22 (m, 6H), 0.86(t, J=6.8 Hz, 3H). Mass (m/z): 607.40 [M+H]⁺. 184: ¹HNMR (400 MHz,CDCl₃) δ 8.64 (d, J=2.0 Hz, 1H), 8.00 (dd, J=2.4, 9.6 Hz, 1H), 7.70 (s,1H), 6.98 (m, 1H), 6.96-6.94 (m, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.75 (d,J=9.6 Hz, 1H), 6.64 (t, J=54.4 Hz, 1H), 5.70 (br, 1H), 5.21 (s, 2H),3.88 (s, 3H), 3.87 (s, 3H), 3.23-3.19 (m, 2H), 2.40 (t, J=6.8 Hz, 2H),2.28-2.19 (m, 2H), 1.48-1.43 (m, 2H), 1.31-1.26 (m, 6H), 0.86 (t, J=6.8Hz, 3H). Mass (m/z): 591.40 [M+H]⁺.

N-(3-((4-(difluoromethyl)-6-(1-(3,4-dimethoxybenzyl)-6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-2-yl)sulfonyl)propyl)acetamide(185)

The titled compound 185 (10 mg, 27% yield) was prepared as white solidfrom 172-1 (28 mg, 0.069 mmol) and N-(3-bromopropyl)acetamide (23 mg,0.13 mmol) according to the procedure for 140. ¹HNMR (400 MHz, CDCl₃) δ8.65 (d, J=2.8 Hz, 1H), 8.00 (dd, J=2.8, 9.6 Hz, 1H), 7.81 (s, 1H), 6.98(d, J=2.0 Hz, 1H), 6.96 (dd, J=2.0, 8.4 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H),6.75 (d, J=10.0 Hz, 1H), 6.64 (t, J=54.4 Hz, 1H), 5.94 (br, 1H), 5.22(s, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.60 (t, J=7.2 Hz, 2H), 3.46 (q,J=6.8 Hz, 2H), 2.17-2.10 (m, 2H), 1.97 (s, 3H). Mass (m/z): 537.21[M+H]⁺.

5,5′-(2,2′-(propane-1,3-diyldisulfonyl)bis(6-(difluoromethyl)pyrimidine-4,2-diyl))bis(1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one)(186)

The titled compound 186 (26 mg, 59% yield) was prepared as white solidfrom 172-1 (69 mg, 0.17 mmol) and 1,3-dibromopropane (10 mg, 0.048 mmol)according to the procedure for 140.

¹HNMR (400 MHz, CDCl₃) δ 8.66 (d, J=2.8 Hz, 1H), 7.96 (dd, J=2.4, 9.6Hz, 1H), 7.81 (s, 1H), 6.97 (d, J=2.0 Hz, 1H), 6.95 (dd, J=2.0, 8.4 Hz,1H), 6.84 (d, J=8.4 Hz, 1H), 6.73 (d, J=10.0 Hz, 1H), 6.60 (t, J=54.4Hz, 1H), 5.19 (s, 2H), 3.88 (t, J=7.2 Hz, 1H), 3.85 (s, 3H), 3.84 (s,3H), 2.61 (qu, J=7.2 Hz, 1H), 1.25 (t, J=6.8 Hz, 1H), Mass (m/z):915.21[M+H]

Synthesis of Compounds 187-200

1-(3,4-dimethoxybenzyl)-5-(6-fluoro-2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(201)

5-(6-(difluoromethyl)-2-(methylsulfinyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(202)

1-(3,4-dimethoxybenzyl)-5-(6-(fluoromethyl)-2-(methylsulfinyl)pyrimidin-4-yl)pyridin-2(1H)-one (203)

Synthesis of Compounds 204-217

Synthesis of compounds 218-222

Synthesis of compounds 223-268

1-(3,4-dimethoxybenzyl)-5-(2-(methylsulfonyl)-6-propionylpyrimidin-4-yl)pyridin-2(1H)-one(269)

5-(6-(1,1-difluoropropyl)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(270)

5-(6-2-(methylsulfonyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(271)

5-(2-((3-(benzyloxy)propyl)sulfonyl)-6-(difluoromethyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(9272) and5-(6-(difluoromethyl)-2-((3-hydroxypropyl)sulfonyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(9273)

Step 1 the title compound 272 was prepared in a yield of 55% (25 mg,0.043 mmol) as a colorless oil from 172-1(29 mg, 0.072 mmol) and((3-bromopropoxy)methyl)benzene (25 mg, 0.11 mmol), according to theprocedure for 140. ¹H NMR (400 MHz, CDCl₃) δ 8.60 (d, J=2.8 Hz, 1H),7.98 (dd, J=2.8, 9.6 Hz, 1H), 7.78 (s, 1H), 7.30 (m, 5H), 6.94 (d, J=2.0Hz, 1H), 6.91 (dd, J=2.0, 8.0 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.58 (t,J=54.4 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 5.14 (s, 2H), 4.46 (s, 2H), 3.86(s, 3H), 3.84 (s, 3H), 3.71-3.68 (m, 2H), 3.61 (t, J=5.6 Hz, 2H),2.26-2.16 (m, 2H). Mass (m/z): 586.23, [M+H]⁺.

Step 2: To a −78° C. stirred solution of 272 (15 mg, 0.026 mmol) inanhydrous CH₂Cl₂ at N₂ atmosphere was added 1M BCl₃ solution in hexane(39 uL, 0.039 mmol), the whole system was kept stirring for another 2hours, warm to rt, 1 mL H₂O was added to quench the reaction, thenconcentrated the solvent and purified by Prep-TLC (PE/EA 2/1) to give 7mg of 9273 as a light yellow solid (54%). ¹H NMR (400 MHz, CDCl₃) δ 8.65(d, J=2.8 Hz, 1H), 8.00 (dd, J=2.4, 9.6 Hz, 1H), 7.81 (s, 1H), 6.96-6.93(m, 2H), 6.87-6.82 (m, 1H), 6.77 (d, J=9.6 Hz, 1H), 6.50 (t, J=54.4 Hz,1H), 5.19 (s, 2H), 4.53 (t, J=6.4 Hz, 1H), 3.88-3.80 (m, 8H), 3.72-3.68(m, 2H), 2.18-2.12 (m, 2H). Mass (m/z): 496.26, [M+H]⁺.

4-(3-(3,4-dimethoxyphenoxy)piperidin-1-yl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine(274)

Step 1: To PPh₃ (0.98 g, 3.75 mmol) in 5 mL of dry THF at 0° C. wasadded DIAD (0.74 mL, 3.75 mmol) dropwise. The solution was allowed tostir for 10 min, then a solution containing tert-butyl3-hydroxypiperidine-1-carboxylate (0.5 g, 2.5 mmol) in THF (2 mL) wasadded and stirred at 0° C. for another 10 min, 3,4-dimethoxyphenol (0.39g, 2.5 mmol) was added, the solution was warmed to r.t overnight,concentrated the solvent, and purified by flash column chromatography(PE/EA 5/1), 0.19 g colorless oil of 274-01 was obtained, yield: 23%,Mass (m/z): 338.48, [M+H]⁺.

Step 2: To a solution of 274-01 (0.39 g, 1.16 mmol) in CH₂Cl₂ (10 mL)was added TFA (3 mL), which was stirred at r.t for 2 hrs, concentratedthe solvent and resolved in ethyl acetate (5 mL) aqueous NaHCO₃ wasadded to neutralize the acid, separate the organic layer and the waterlayer was extracted with ethyl acetate for three times, combined theorganic phase, dried, concentrated and purified by flash columnchromatography (CH₂Cl₂/MeOH 10/1). 0.27 g yellow oil of 274-02 wasobtained, yield: 100%. Mass (m/z): 238.20, [M+H]⁺.

Step 3: 274-02 (38 mg, 0.16 mmol), 49-01 (30 mg, 0.13 mmol) and K₂CO₃(28mg, 0.2 mmol) was mixed together in dry DMF (2 mL) in a microwave tube,the reaction was microwaved at 90° C. for 2 hrs. cooled to r.t. waterwas added, and the organic layer was extracted with ethyl acetate forthree times, the organic layer was combined, dried and further purifiedby flash column chromatography (EA/PE 1/8) to give 54 mg of 274-03 as acolorless oil, yield: 96%. Mass (m/z): 430.15, [M+H]⁺.

Step 4: the title compound 274 was prepared in a yield of 59% as a whitesolid from 274-03 (27 mg, 0.063 mmol) and Oxone (0.19 g, 0.31 mmol)according to the procedure for 71. ¹H NMR (400 MHz, DMSO-d₆) δ 7.57 (s,1H), 6.83 (d, J=8.4 Hz, 1H), 6.53-6.52 (m, 1H), 6.47-6.41 (m, 1H), 4.62(m, 1H), 4.54-4.42 (m, 1H), 4.28-4.21 (m, 1H), 4.07-4.00 (m, 1H),3.91-3.85 (m, 1H), 3.68 (s, 6H), 3.13 (s, 3H), 2.02-1.98 (m, 2H),1.88-1.82 (m, 2H). Mass (m/z): 462.20 [M+H]⁺.

6-(1-(3,4-dimethoxybenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-2-(methylsulfonyl)pyrimidin-4(3H)-one(275)

Step 1: A mixture of 2.25 g (0.025 mol) of N-methylthiourea, 2.7 g (0.05mol) of sodium methylate, 10 mL of MeOH and 4.0 g (0.025 mol) of malonicacid diethyl ester was boiled for 3 hours under reflux, 3.55 g (0.025mol) of was then added dropwise at about 50° C. and the mixture wasstirred for a further 0.5 hrs at 50° C. The salt which crystallized outwas filtered off and was then dissolved in 20 mL of water. The solutionwas neutralized by adding glacial acetic acid, the precipitate was thenfiltered off, and 3 g (0.017 mol) of 275-01 was obtained as a whitesolid, yield: 69.8%. Mass (m/z): 172.03, [M+H]⁺.

Step 2: The titled compound 275-02 was prepared in a yield of 67.7% (0.9g, 4.72 mmol) as a white solid from 275-01(1.2 g, 6.97 mmol) andphosphorus oxychloride (10 ml) according to the procedure for 49-01.Mass (m/z): 190.65, [M+H]⁺.

Step 3: The titled compound 275-03 was prepared in a yield of 85.4%(1.06 g, 4.03 mmol) as a white solid from 275-02 (0.9 g, 4.72 mmol)according to the procedure for 99-01. Mass (m/z): 264.30, [M+H]⁺.

Step 4: The titled compound 275-04 was prepared without purification(1.06 g) as a white solid from 275-03 (1.06 g, 4.03 mmol) according tothe procedure for 99-02. Mass (m/z): 250.23, [M+H]⁺.

Step 5: The titled compound 275 was prepared in a yield of 6.6% (15 mg,0.035 mmol) as a light yellow oil from 275-04 (0.13 g, 0.53 mmol) and4-(bromomethyl)-1,2-dimethoxybenzene (0.15 g, 0.64 mmol) according tothe procedure for 99-01. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, J=2.8 Hz,1H), 7.70 (dd, J=2.4, 6.8 Hz, 1H), 6.87 (m, 3H), 6.71 (d, J=9.6 Hz, 1H),6.61 (s, 1H), 5.10 (s, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 3.79 (s, 3H),3.22 (s, 3H). Mass (m/z): 432.35, [M+H]⁺.

1-(3,4-dimethoxybenzyl)-5-(2-((4-hydroxybutyl)sulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(276)

Step 1: The title compound 276-01 was prepared in a yield of 33.3% (25mg, 0.04 mmol) as a colorless oil from 140-1 (50 mg, 0.12 mmol) and((4-bromobutoxy)methyl)benzene (44 mg, 0.18 mmol), according to theprocedure for 140. Mass (m/z): 618.47, [M+H]⁺.

Step 2. The titled compound 276 was prepared in a yield of 47.5% (10 mg,0.019 mmol) as a white solid from 276-01(0.013 mmol) according to theprocedure for 273. ¹H NMR (400 MHz, CDCl₃) δ 8.72 (d, J=2.4 Hz, 1H),7.99 (dd, J=2.4, 9.6 Hz, 1H), 7.81 (s, 1H), 6.96-6.92 (m, 2H), 6.86 (d,J=8.0 Hz, 1H), 6.77 (d, J=9.6 Hz, 1H), 5.21 (s, 2H), 3.88 (s, 3H), 3.87(s, 3H), 3.71 (t, J=6.0 Hz, 2H), 3.66-3.62 (m, 2H), 2.06-1.99 (m, 2H),1.80-1.73 (m, 2H). Mass (m/z): 528.59, [M+H]⁺.

5-(2-((3-(benzyloxy)-3-phenylpropyl)sulfinyl)-6-(difluoromethyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(277) and5-(2-((3-(benzyloxy)-3-phenylpropyl)sulfonyl)-6-(difluoromethyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(278)

The title compound 277 (8 mg, 0.012 mmol) and 278 (10 mg, 0.015 mmol)was prepared as a colorless oil from 172-1 (55 mg, 0.12 mmol) and(1-(benzyloxy)-3-chloropropyl)benzene (47 mg, 0.18 mmol), according tothe procedure for 140. 277: ¹HNMR (400 MHz, CDCl₃) δ 8.53 (s, 1H), 7.97(m, 1H), 7.71 (m, 1H), 7.65 (s, 1H), 7.53 (m, 1H), 7.37-7.28 (m, 8H),7.23 (m, 1H), 6.94 (m, 1H), 6.90-6.87 (m, 1H), 6.83-6.80 (dd, J=1.6, 8.4Hz, 1H), 6.73-6.70 (m, 1H), 4.55 (q, J=4.4 Hz, 1H), 4.48-4.40 (m, 1H),4.32-4.15 (m. 2H), 3.86 (d, J=2.4 Hz, 3H), 3.85 (s, 3H), 3.40-3.32 (m,1H), 3.26-3.08 (m, 1H). Mass (m/z): 646.45[M+H]⁺; 278: ¹H NMR (400 MHz,CDCl3) δ 8.58 (d, J=2.8 Hz, 1H), 7.97 (dd, J=2.4, 9.6 Hz, 1H), 7.76 (s,1H), 7.39-7.29 (m, 7H), 7.28 (m, 3H), 6.94 (d, J=2.0 Hz, 1H), 6.90 (dd,J=1.6, 8.0 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.71 (d, J=9.6 Hz, 1H), 6.54(t, J=54.4 Hz, 1H), 5.14 (d, J=2.0 Hz, 2H), 4.56 (dd, J=4.8, 8.0 Hz,1H), 4.48 (d, J=11.6 Hz, 1H), 4.27 (d, J=12.0 Hz, 1H), 3.86 (s, 3H),3.84 (s, 3H), 3.82-3.74 (m, 1H), 3.66-3.57 (m, 1H), 2.38-2.23 (m, 2H).Mass (m/z): 662.53, [M+H]⁺.

5-(2-((3-chloro-3-phenylpropyl)sulfonyl)-6-(difluoromethyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(279)

The titled compound 279 was prepared in a yield of 100% (14 mg, 0.024mmol) as a white solid from 278 (16 mg, 0.024 mmol) according to theprocedure for 273. ¹H NMR (400 MHz, CDCl₃) δ 8.63 (d, J=2.0 Hz, 1H),7.98 (dd, J=1.6, 9.6 Hz, 1H), 7.81 (s, 1H), 7.38-7.37 (m, H), 6.95 (m,1H), 6.93 (2.0, 8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=9.2 Hz,1H), 6.60 (t, J=54.4 Hz, 1H), 5.19 (s, 2H), 5.11 (dd, J=5.6, 8.0 Hz,1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.82-3.75 (m, 1H), 3.71-3.63 (m, 1H),2.71-2.57 (m, 2H). Mass (m/z): 590.42, [M+H]⁺.

5-(2-((3-(benzyloxy)-3-phenylpropyl)sulfinyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(280) and5-(2-((3-(benzyloxy)-3-phenylpropyl)sulfonyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(281)

The title compound 280 (4.8 mg, 0.0072 mmol) and 281 (15 mg, 0.022 mmol)was prepared as white solid from 140-1 (55 mg, 0.12 mmol) and(1-(benzyloxy)-3-chloropropyl)benzene (44 mg, 0.17 mmol), according tothe procedure for 140. 280: ¹H NMR (400 MHz, CDCl₃) δ 8.70 (t, J=2.4 Hz,1H), 7.99 (td, J=2.4, 9.6 Hz, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.39-7.22 (m,10H), 6.97 (t, J=2.4 Hz, 1H), 6.93-6.90 (m, 1H), 6.83 (dd, J=1.2 8.4 Hz,1H), 6.77 (dd, J=0.8, 9.6 Hz, 1H), 5.25-5.11 (m, 2H), 4.58 (q, J=4.0 Hz,0.7H), 4.49-4.42 (m, 1.57H), 4.29 (d, J=12.0 Hz, 0.60H), 4.21 (d, J=12.0Hz, 0.55H), 3.87 (d, J=2.4 Hz, 3H), 3.85 (s, 3H), 3.46-3.38 (m, 1H),3.33-3.26 (m, 0.70H), 3.23-3.16 (m, 0.70H), 2.48-2.31 (m, 1H), 2.14-2.00(m, 1H). Mass (m/z): 664.28, [M+H]⁺. 281: ¹H NMR (400 MHz, CDCl₃) δ 8.87(d, J=2.0 Hz, 1H), 8.01 (dd, J=2.0, 9.6 Hz, 1H), 7.80 (s, 1H), 7.40-7.26(m, 10H), 6.95 (s, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.84-6.79 (m, 2H), 5.19(s, 2H), 4.57 (m, 1H), 4.49 (d, J=11.6 Hz, 1H), 4.27 (d, J=11.6 Hz, 1H),3.87-3.79 (m, 7H), 3.69-3.62 (m, 1H), 2.41-2.25 (m, 2H); Mass (m/z):680.28, [M+H]⁺.

5-(2-((3-(benzyloxy)-3-phenylpropyl)sulfonyl)-6-(fluoromethyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(282)

Step 1: The titled compound 282-01 was prepared without purification asa yellow syrup from 161 (16 mg, 0.037 mmol) according to the procedurefor 140-1. Mass (m/z): 388.24, [M+H]⁺.

Step 2: The title compound 282 was prepared in a yield of 14% (3.4 mg,0.0053 mmol) as a colorless oil from 282-01 (0.037 mmol) and(1-(benzyloxy)-3-chloropropyl)benzene (15 mg, 0.056 mmol), according tothe procedure for 140. ¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1H), 7.97 (d,J=9.6 Hz, 1H), 7.72-7.71 (m, 1H), 7.66 (s, 1H), 7.54-7.54 (m, 1H),7.38-7.26 (m, 9H), 6.93 (s, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.83 (d, J=8.0Hz, 1H), 6.70 (d, J=9.6 Hz, 1H), 5.54 (s, 1H), 5.42 (s, 1H), 5.17-5.09(m, 2H), 4.56-4.45 (m, 2H), 4.29-4.25 (m, 1H), 3.86 (s, 3H), 3.85 (s,3H), 3.79-3.72 (m, 1H), 3.61-3.54 (m, 1H), 2.34-2.21 (m, 2H). Mass(m/z). 644.45, [M+H]⁺.

5-(6-(difluoromethyl)-2-(3-(2-fluorobenzyloxy)-3-phenylpropylsulfinyl)pyrimidin-4-yl)-1-(3-fluoro-4-methoxybenzyl)pyridin-2(1H)-one(283) and5-(6-(difluoromethyl)-2-(3-(2-fluorobenzyloxy)-3-phenylpropylsulfonyl)pyrimidin-4-yl)-1-(3-fluoro-4-methoxybenzyl)pyridin-2(1H)-one(284)

Step 1. The compound 283-01 was prepared in a yield of 99% as 285 mgyellow solid from compound 167 (292 mg, 0.67 mmol) according to theprocedure for 140-01. Mass (m/z): 394.41[M+H]⁺.

Step 4. The titled compound 283 (25.5 mg, 16.7%) and 284 (5.1 mg, 3.3%)were prepared as both yellow solid from 283-01 (100 mg, 025 mmol) and1-((3-chloro-1-phenylpropoxy)methyl)-2-fluorobenzene (106 mg, 0.38 mmol)according to the procedure for 140. 283: ¹HNMR (400 MHz, CDCl₃) δ 8.60(s, 1H), 7.99 (d, J=9.6 Hz, 1H), 7.70 (s, 1H), 7.32-7.29 (m, 6H),7.10-7.06 (m, 3H), 7.00-6.88 (m, 2H), 6.72 (d, J=9.6 Hz, 1H), 6.58 (t,J=54.5 Hz, 1H), 5.13 (m, 2H), 4.57 (m, 1H), 4.50-4.26 (m, 3H), 3.84 (s,3H), 3.42-3.11 (m, 2H), 2.43-2.30 (m, 1H), 2.09-2.00 (m, 1H). Mass(m/z): 652.20 [M+H]⁺. 284: ¹HNMR (400 MHz, CDCl₃) δ 8.57 (s, 1H), 7.99(d, J=9.6 Hz, 1H), 7.81 (s, 1H), 7.38-7.32 (m, 7H), 7.10 (m, 3H), 7.00(t, J=9.6 Hz, 1H), 6.91 (t, J=9.6 Hz, 1H), 6.75 (d, J=9.6 Hz, 1H), 6.55(t, J=54.4 Hz, 1H), 5.13 (s, 2H), 4.56 (m, 1H), 4.49 (d, J=12.0 Hz, 1H),4.37 (d, J=12.0 Hz, 1H), 3.85 (s, 3H), 3.84-3.76 (m, 1H), 3.65-3.57 (m,1H), 2.34-2.26 (m, 2H). Mass (m/z): 668.21[M+H]⁺

5-(2-(3-(2,4-difluorobenzyloxy)-3-phenylpropylsulfinyl)-6-(difluoromethyl)pyrimidin-4-yl)-1-(3-fluoro-4-methoxybenzyl)pyridin-2(1H)-one(285) and5-(2-(3-(2,4-difluorobenzyloxy)-3-phenylpropylsulfonyl)-6-(difluoromethyl)pyrimidin-4-yl)-1-(3-fluoro-4-methoxybenzyl)pyridin-2(1H)-one(286)

The titled compound 285 (14.3 mg, 10.3%), and 286 (15.0 mg, 8.1%) wereprepared as both yellow solid from 283-01 (100 mg, 0.25 mmol) and1-((3-chloro-1-phenylpropoxy)methyl)-2,4-difluorobenzene (112 mg, 0.38mmol) according to the procedure for 140. 285: ¹HNMR (400 MHz, CDCl₃) δ8.62 (s, 1H), 7.98 (d, J=9.2 Hz, 1H), 7.70 (s, 1H), 7.33-7.28 (m, 6H),7.12 (d, J=9.6 Hz, 2H), 6.91 (t, J=8.4 Hz, 1H), 6.83-6.72 (m, 3H), 6.59(t, J=54.4 Hz, 1H), 5.15 (s, 2H), 4.56 (m, 1H), 4.44-4.21 (m, 3H), 3.85(s, 3H), 3.40-3.11 (m, 2H), 2.46-2.24 (m, 1H). Mass (m/z): 670.19[M+H]⁺.286: ¹HNMR (400 MHz, CDCl₃) δ 8.57 (s, 1H), 8.00 (d, J=9.2 Hz, 1H), 7.81(s, 1H), 7.39-7.29 (m, 6H), 7.10 (d, J=10.4 Hz, 2H), 6.93 (t, J=8 Hz,1H), 6.84 (t, J=8 Hz, 1H), 6.79 (m, 2H), 6.56 (t, J=54.4 Hz, 1H), 5.15(s, 2H), 4.57 (m, 1H), 4.44 (d, J=11.6 Hz, 1H), 4.34 (d, J=12.0 Hz, 1H),3.86 (s, 3H), 3.80-3.72 (m, 1H), 3.64-3.56 (m, 1H), 2.34-2.26 (m. 2H).Mass (m/z): 686.16[M+H]⁺.

5-(6-(difluoromethyl)-2-((3-hydroxy-3-phenylpropyl)sulfonyl)pyrimidin-4-yl)-1-(3-fluoro-4-methoxybenzyl)pyridin-2(1H)-one(287)

The title compound 287 (13 mg, 0.023 mmol) was prepared as a white solidfrom 283-01 (59 mg, 0.15 mmol) and2-(3-chloro-1-phenylpropoxy)tetrahydro-2H-pyran (58 mg, 0.23 mmol),according to the procedure for 140. ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d,J=2.4 Hz, 1H), 8.01 (dd, J=2.4, 9.6 Hz, 1H), 7.83 (s, 1H), 7.38-7.29 (m,5H), 7.13-7.10 (m, 2H), 6.94 (t, J=8.4 Hz, 1H), 6.79 (d, J=9.6 Hz, 1H),6.61 (t, J=54.4 Hz, 1H), 5.18 (s, 2H), 4.96 (dd, J=5.2, 7.6 Hz, 1H),3.87 (s, 3H), 3.82-3.66 (m, 2H), 2.37-2.25 (m, 2H). Mass (m/z): 560.13,[M+H]⁺.

N-((3s,5s,7s)-adamantan-1-yl)-4-((4-(difluoromethyl)-6-(1-(3,4-dimethoxybenzyl)-6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-2-yl)sulfonyl)butanamide(288)

The titled compound 288 (3.2 mg, 5.6% yield) was prepared as white solidfrom 172-1

(58 mg, 0.14 mmol) and N-((3s,5s,7s)-adamantan-1-yl)-4-bromobutanamide(78 mg, 0.26 mmol) according to the procedure for 140. ¹HNMR (400 MHz,CDCl₃) δ 8.83 (d, J=2.8 Hz, 1H), 7.98 (dd, J=2.4, 9.6 Hz, 1H), 7.81 (s,1H), 7.01-6.96 (m, 2H), 6.86 (d, J=8.4 Hz, 1H), 6.74 (d, J=4.8 Hz, 1H),6.65 (t, J=54.4 Hz, 1H), 5.35 (m, 1H),5.27 (s, 3H), 3.87 (s, 3H), 3.86(s, 3H), 3.65 (t, J=7.2 Hz, 2H), 2.35 (t, J=6.4 Hz, 2H), 2.23 (m, 3H),2.03 (m, 5H), 1.96 (m, 6H) 1.63 (m, 3H). Mass (m/z): 657.51[M+H]⁺;

N-((3s,5s,7s)-adamantan-1-yl)-4-((4-(1-(3,4-dimethoxybenzyl)-6-oxo-1,2,3,6-tetrahydropyridin-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl)sulfonyl)butanamide(289)

EC50=0.42 nM

The titled compound (9 mg, 16% yield) was prepared as a white solid from140-01 (40 mg, 0.094 mmol) andN-((1S,3s)-adamantan-1-yl)-4-bromobutanamide (30 mg, 0.1 mmol) accordingto the procedure for 140. ¹H NMR (400 MHz, CDCl₃) δ 8.85 (d, 1H, J=2.4Hz), 7.96 (dd, 1H, J=2.4, 9.6 Hz), 7.81 (s, 1H), 6.99 (d, 1H, J=2.0 Hz),6.70 (dd, 11H, J=2.0, 4.0 Hz), 6.84 (d, 1H, J=8.0 Hz), 6.72 (d, 1H,J=9.6 Hz), 5.26 (s, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.67 (t, 2H, J=7.2Hz), 2.36 (t, 2H, J=6.8 Hz), 2.26-2.22 (m, 2H), 2.04-2.01 (m, 3H),1.96-1.95 (m, 6H), 1.27-1.24 (m, 6H). ¹³C NMR (100 MHz, CDCl₃): δ169.89, 166.32, 165.48, 162.06, 157.76, 157.41, 149.46, 141.88, 135.81,130.02, 127.87, 121.46, 121.22, 113.16, 112.08, 111.99, 111.36, 56.15,56.08, 53.15, 52.32, 50.99, 41.79, 36.39, 35.15, 29.51, 27.35, 25.67,22.83, 18.83. HRMS (ESI): calculated for [C₃₃H₃₈F₃N₄O₆S⁺], 675.2459,found 675.2479.

2-(3-(benzyloxy)-3-phenylpropylsulfinyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine(290) and2-(3-(benzyloxy)-3-phenylpropylsulfonyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine(291)

The titled compounds 290 (13.5 mg, 17.2% yield) and 291 (21.2 mg, 26.2%yield) was prepared as both white solid from 1-02 (30 mg, 0.12 mmol) and(1-(benzyloxy)-3-chloropropyl)benzene (47 mg, 0.18 mmol) according tothe procedure for 140. 290: ¹HNMR (400 MHz, CDCl₃) δ 7.98 (d, J=4.4 Hz,1H), 7.79 (d, J=1.6 Hz, 1H), 7.71-7.69 (m, 1H), 7.35-7.28 (m, 8H),7.24-7.22 (m, 3H), 4.57 (q, J=4.0 Hz, 1H), 4.49-4.42 (m, 1H), 4.30 (d,J=12.0 Hz, 1H), 4.22 (d, J=12 Hz, 1H), 3.46-3.38 (m, 1H), 3.32-3.15 (m,1H), 2.48-2.32 (m, 1H). Mass (m/z): 503.27[M+H]⁺. 291: ¹HNMR (400 MHz,CDCl₃) δ 7.99 (d, J=3.6 Hz, 1H), 7.89 (s, 1H), 7.73 (d, J=5.2 Hz, 1H),7.38-7.28 (m, 10H), 7.23 (t, J=4.4 Hz, 1H), 4.58 (q, J=4.0 Hz, 1H), 4.51(d, J=12.0 Hz, 1H), 4.30 (d, J=12.0 Hz, 1H), 3.89-3.81 (m, 1H),3.72-3.6(m, 1H), 2.44-2.31 (m, 2H). Mass (m/z): 519.28[M+H]⁺.

2-((3-chloro-3-phenylpropyl)sulfonyl)-4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidine(292)

The titled compound 292 was prepared in a yield of 71.2% (13 mg, 0.029mmol) as a light yellow oil from 291 (18.8 mg, 0.036 mmol) according tothe procedure for 273. ¹HNMR (400 MHz, CDCl₃) δ 8.03 (dd, J=1.2, 4.0 Hz,JH), 7.94 (s, 1H), 7.77 (dd, J=1.2, 4.8 Hz, 1H), 7.42-7.33 (m, 5H),7.31-7.27 (m, 1H), 5.12 (m, 1H), 3.88-3.80 (m, 1H), 3.77-3.69 (m, 1H),2.76-2.67 (m, 2H). Mass (m/z): 447.17, [M+H]⁺.

5-(2-((3-(benzyloxy)-3-phenylpropyl)sulfonyl)quinazolin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(293)

Step 1: The titled compound 293-01 was prepared in a yield of 63.7%(0.87 g, 3.2 mmol) as a white solid from 2,4-dichloroquinazoline (1.0 g,5.02 mmol) and (6-methoxypyridin-3-yl)boronic acid (0.52 g, 3.35 mmol)according to the procedure for 99-01. Mass (m/z): 272.17, [M+H]⁺.

Step 2: The titled compound 293-02 was prepared as described above forthe synthesis of 140-1, NaSMe was used instead, 0.6 g of yellow solidwas obtained, which was used directly in the next step without furtherpurification. Mass (m/z): 284.13, [M+H]⁺.

Step 3: The titled compound 293-03 was prepared without purification(0.5 g) as a yellow solid from 293-02 (0.6 g) according to the procedurefor 99-02. Mass (m/z): 270.20, [M+H]⁺.

Step 4: The titled compound 293-04 was prepared in a yield of 2.4% (16mg, 0.035 mmol) as a colorless oil from 293-03 (0.4 g, 1.48 mmol) and4-(bromomethyl)-1,2-dimethoxybenzene (0.34 g, 1.48 mmol) according tothe procedure for 99-01. Mass (m/z): 452.21, [M+H]⁺.

Step 5: The titled compound 293-05 was prepared without purification asa yellow syrup from 293-04 (16 mg, 0.035 mmol) according to theprocedure for 140-1. Mass (m/z): 406.18, [M+H]⁺.

Step 6: The title compound 293 was prepared in a yield of 8.57% (2.0 mg,0.003 mmol) as a colorless oil from 293-05 (0.035 mmol) and(1-(benzyloxy)-3-chloropropyl)benzene (14 mg, 0.053 mmol), according tothe procedure for 140. ¹H NMR (400 MHz, CDCl₃) δ 8.21 (m, 1H), 8.07 (m,3H), 7.87 (m, 1H), 7.75-7.71 (m, 1H), 7.36-7.26 (m, 11H), 6.98 (s, 1H),6.94-6.92 (m, 1H), 6.84-6.82 (m, 1H), 6.77-6.75 (m, 1H), 5.18 (s, 2H),4.58 (t, J=5.6 Hz, 1H), 4.48 (d, J=1 Hz, 1H), 4.29 (d, J=11.2 Hz, 1H),3.88 (s, 3H), 3.86 (s, 3H), 3.75-3.67 (m, 2H), 2.40-2.32 (m, 2H). Mass(m/z): 662.32, [M+H]⁺.

5-(2-(3-(benzyloxy)-3-phenylpropylsulfinyl)-6-methylpyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(294) and5-(2-(3-(benzyloxy)-3-phenylpropylsulfonyl)-6-methylpyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(295)

Step 1: A mixture of 4,6-dichloro-2-(methylthio)pyrimidine (6.7 g, 0.034mol), 6-methoxypyridin-3-ylboronic acid (3.5 g, 0.023 mol), Na₂CO₃(10.8g, 0.10 mol) and Pd(PPh₃)₄ (1.0 g, 0.86 mmol) in 1,4-dioxane (50 mL) andH₂O (25 mL) was heated to 90° C. The reaction mixture was stirred for 3h under N₂. Evaporation to remove the 1,4-dioxane, the mixture wasdiluted by H₂O. The aqueous layer was extracted by EtOAc for 3 times.The organic layer was combined, washed by brine, dried over Na₂SO₄ andfurther purified by silica gel column chromatography (PE:EA=300:1 to100:1) to give 5.3 g of 294-01 as white solid (86.9/6). Mass (m/z);269.16[M+H]⁺.

Step 2. The compound 294-02 was prepared in a yield of 92.0% (4.62 g) aslight yellow solid from 294-01 (5.3 g, 19.8 mmol) according to theprocedure for 99-02. Mass (m/z): 254.16[M+H]⁺.

Step 3. The compound 294-03 was prepared in a yield of 53.6% (3.87 g) aswhite solid from 294-02 (4.52 g, 17.9 mmol) according to the procedurefor 85-01. Mass (m/z): 404.20[M+H]⁺.

Step 4. The compound 294-04 was prepared in a yield of 82.8% (3.46 g) asyellow solid from 294-3 (3.87 g, 9.6 mmol) and Oxone (11.8 g, 19.2 mmol)according to the procedure for 85. Mass (m/z): 436.59[M+H]⁺.

Step 5. Pd(dppf)C12 (214 mg, 0.29 mmol) was added to the solution of294-04 (1.3 g, 2.98 mmol), methylboronic acid (180 mg, 3.01 mmol) andK₃PO₄ (1.58 g 7.44 mmol) in THF (15 mL) under N₂. The mixture was heatedto 90° C. and stirred overnight. The reaction mixture was diluted byH₂O, extracted by EtOAc for 3 times. The organic layer was combined,washed by brine, dried over Na₂SO₄. Evaporation to remove the solvent,further purified by pre-TLC (DCM:MeOH=20:1) to give 77.8 mg of 294-05 aslight yellow oil (5.9%). Mass (m/z): 416.12, [M+H]⁺.

Step 6. The compound 294-06 was prepared as yellow oil from compound294-05 (78 mg, 0.19 mmol) according to the procedure for 140-01. Mass(m/z): 370.11 [M+H]⁺.

Step 7. The titled compound 294(5.2 mg, 18.2%), and 295 (3.2 mg, 10.9%)were prepared as White solid and colorless oil from 294-06 (0.19 mmol)and (1-(benzyloxy)-3-chloropropyl)benzene (74 mg, 0.28 mmol) accordingto the procedure for 140. 294: ¹HNMR (400 MHz, CDCl₃) δ 8.44 (s, 1H),7.91 (d, J=9.6 Hz, 1H), 7.72-7.51 (m, 1H), 7.36-7.29 (m, 8H), 7.23 (m,2H), 6.94 (s, 1H), 6.89-6.86 (m, 1H), 6.81 (d, J=8 Hz, 1H), 6.69 (dd,J=3.2, 9.6 Hz, 1H), 5.12 (m, 2H), 4.56 (q, J=4 Hz, 1H), 4.47-4.40 (m,1H), 4.32-4.17 (m. 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.35-3.09 (m, 2H),2.60 (s, 3H), 2.41-2.31 (m, 1H). Mass (m/z); 610.46 [M+H]⁺; 295: ¹HNMR(400 MHz, CDCl₃) δ 8.44 (d, J=2.8 Hz, 1H), 7.90 (dd, J=2.4, 9.6 Hz, 1H),7.38-7.27 (m, 10H), 6.93 (d, J=2.0 Hz. 1H), 6.88 (dd, J=2.0. 8.0 Hz,1H), 6.82 (d, J=8.4 Hz, 1H), 6.68 (dd, J=9.6 Hz, 1H), 5.12 (m, 2H), 4.56(m, 1H), 4.48 (d, J=11.6 Hz, 1H), 4.29 (d, J=11.6 Hz, 1H), 3.86 (s, 3H),3.84 (s, 3H), 3.82-3.72 (m, 1H), 3.62-3.55 (m, 1H), 2.61 (s, 3H),2.35-2.20 (m, 3H). Mass (m/z): 626.48 [M+H]⁺.

1-(3,4-dimethoxybenzyl)-5-(6-(2-fluorophenyl)-2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(296)

The titled compound 296 (0.13 g, 76%) were prepared as brown solid from294-04 (0.15 g, 0.35 mmol) and (2-fluorophenyl)boronic acid (59 mg, 0.42mmol) according to the procedure for 294-05. ¹H NMR (400 Hz, CDCl₃) δ8.58 (s, 1H), 8.26 (t, J=6.8 Hz, 1H), 8.09-8.01 (m, 2H), 7.58-7.53 (m,1H), 7.35 (t, J=7.2 Hz, 1H), 7.24 (m, 1H), 7.00-6.94 (m, 2H), 6.87-6.85(m, 1H), 6.75-6.74 (m, 1H), 5.21 (s, 2H), 3.89 (s, 3H), 3.87 (s, 3H),3.40 (s, 3H). Mass (m/z): 496.30, [M+H]⁺.

5-(2-((3-(benzyloxy)-3-phenylpropyl)sulfinyl)-6-(2-fluorophenyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(297) and5-(2-((3-(benzyloxy)-3-phenylpropyl)sulfonyl)-6-(2-fluorophenyl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(298)

Step 1: The titled compound 297-01 was prepared without purification asa yellow solid from 304 (70 mg, 0.14 mmol) according to the procedurefor 140-01. Mass (m/z): 450.18, [M+H]⁺.

Step 2: The title compound 297 (13 mg, 0.019 mmol) and 298 (15 mg, 0.021mmol) was prepared as a colorless oil from 297-01 (48 mg, 0.11 mmol) and(1-(benzyloxy)-3-chloropropyl)benzene (44 mg, 0.17 mmol), according tothe procedure for 140. 297: ¹H NMR (400 MHz, CDCl3) δ 8.60 (m, 1H), 8.20(m, 1H), 8.01-7.95 (m, 2H), 7.53 (m, 1H), 7.31-7.20 (m, 12H), 6.87-6.92(m, 2H), 6.83-6.74 (m, 2H), 5.19 (s, 2H), 4.59-4.57 (m, 0.6H), 4.49-4.41(m, 1.49H), 4.32 (d, J=11.6 Hz, 0.57H), 4.21 (d, J=11.6 Hz, 0.54H),3.87, 3.85 (s*2, 6H), 3.43-3.20 (m, 2H), 2.43-2.37 (m, 2H). Mass (m/z):690.29, [M+H]⁺. 298: ¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 1H), 8.20 (t,J=7.6 Hz, 1H), 8.06 (s, 1H), 7.99 (d, J=9.6 Hz, 1H), 7.56-7.51 (m, 1H),7.35-7.23 (m, 12H), 6.96 (s, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.84-6.82 (m,1H), 6.73 (d, J=9.6 Hz, 1H), 5.16 (s, 2H), 4.59-4.56 (m, 1H), 4.50 (d,J=11.6 Hz, 1H), 4.30 (d, J=11.6 Hz, 1H), 3.91-3.85 (m, 7H), 3.69-3.62(m, 1H), 2.40-2.32 (m, 2H). Mass (m/z): 706.27, [M+H]⁺.

5-(2-((3-(benzyloxy)-3-phenylpropyl)sulfinyl)-6-(thiophen-2-yl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(299) and5-(2-((3-(benzyloxy)-3-phenylpropyl)sulfonyl)-6-(thiophen-2-yl)pyrimidin-4-yl)-1-(3,4-dimethoxybenzyl)pyridin-2(1H)-one(300)

Step 1: The title compound 299-01 (0.15 g, 0.31 mmol) was prepared in ayield of 91% as a brown solid from 294-04 (0.15 g, 0.34 mmol) andthiophen-2-ylboronic acid (52 mg, 0.41 mmol), according to the procedurefor 294-05. Mass (m/z): 484.10, [M+H]⁺.

Step 2: The titled compound 299-02 was prepared without purification asa yellow solid from 299-01 (0.15 g, 0.31 mmol) according to theprocedure for 140-1. Mass (m/z): 438.07, [M+H]⁺.

Step 3: The title compound 299 (6 mg, 0.0089 mmol) and 300 (10 mg, 0.014mol) was prepared as colorless oil from 299-02 (0.31 mmol) and(1-(benzyloxy)-3-chloropropyl)benzene (96 mg, 0.37 mmol), according tothe procedure for 140. 299: ¹H NMR (400 MHz, CDCl₃) δ 8.64 (s, 1H), 8.00(d, J=8.4 Hz, 1H), 7.89 (m, 1H), 7.62 (t, J=4.8 Hz, 2H), 7.34-7.19 (m,11H), 6.97 (m, 1H), 6.92 (dd, J=7.6 Hz, 1H), 6.82 (m, 1H), 6.76 (d,J=8.4 Hz, 1H), 5.24-5.11 (m, 2H), 4.58-4.56 (m, 0.58H), 4.50-4.41 (m,1.62H), 4.32 (d, J=11.6 Hz, 0.60H), 4.21 (d, J=11.6 Hz, 0.62H), 3.87 (s,3H), 3.85 (s, 3H), 3.47-3.40 (m, 1H), 3.35-3.29 (m, 0.54H), 3.25-3.19(m, 0.53H), 2.46-2.34 (n, 1H), 2.15-2.10 (m, 1H). Mass (m/z): 678.17,[M+H]⁺. 300: ¹H NMR (400 MHz, CDCl₃) δ 8.58 (s, 1H), 7.95 (d, J=7.6 Hz,1H), 7.87 (d, J=2.8 Hz, 1H), 7.65 (s, 1H), 7.60 (d, J=5.2 Hz, 1H),7.39-7.26 (m, 10H), 7.17 (t, J=4.0 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J=8.4Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.73 (d, J=8.8 Hz, 1H), 5.17 (s, 2H),4.60-4.57 (m, 1H), 4.51 (d, J=11.6 Hz, 1H), 4.31 (d, J=12.0 Hz, 1H),3.92-3.79 (m, 7H), 3.70-3.63 (m, 1H), 2.42-2.30 (m, 2H). Mass (m/z):694.20, [M+H]⁺.

3-fluoro-1-(3-fluoro-4-methoxybenzyl)-5-(2-(3-(2-fluorobenzyloxy)-3-phenylpropylsulfinyl)thieno[2,3-d]pyrimidin-4-yl)pyridin-2(1H)-one(301) and3-fluoro-1-(3-fluoro-4-methoxybenzyl)-5-(2-(3-(2-fluorobenzyloxy)-3-phenylpropylsulfonyl)thieno[2,3-d]pyrimidin-4-yl)pyridin-2(1H)-one(302)

Step 1. The compound 301-01 was prepared in a yield of 70.6% as whitesolid (3.73 g) from 5-bromo-3-fluoropyridin-2(1H)-one (3.0 g, 16.0 mmol)and 4-(bromomethyl)-2-fluoro-1-methoxybenzene (3.8 g, 17.0 mmol)according to the procedure for 165-04. Mass (m/z): 329.98, [M+H]⁺.

Step 2. Pd(PPh₃)₂Cl₂(442 mg, 0.60 mmol) was added to the mixture of301-01 (2.0 g, 6.05 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.1 g, 12.1mmol) and KOAc (1.78 g, 18.2 mmol) in 1,4-dioxane (40 mL) under N₂. Thenthe mixture was heated to 80° C., stirred for 3 h. Evaporation to removethe solvent, the residue was washed by EtOAc to give the mixture of301-02 and 301-03 as brown powder in a yield of 98%. The product wasused without further purification. 301-2: Mass (m/z): 379.17, [M+H]⁺,301-03: Mass (m/z).296.01 [M+H]⁺.

Step 3. The compound 301-04 was prepared in a yield of 69.8% as yellowsolid (77.5 mg) from the mixture (100 mg) of 301-02 and 301-03 and2,4-dichlorothieno[2,3-d]pyrimidine (100 mg, 0.3 mmol) according to theprocedure for 99-01. Mass (m/z): 419.99, [M+H]⁺.

Step 4. The compound 301-05 was prepared as yellow oil from compound301-04 (77.5 mg, 0.18 mmol) according to the procedure for 140-01. Mass(m/z): 418.01 [M+H]⁺.

Step 5. The titled compound 301 (8.5 mg, 6.3%), and 302 (5.5 mg, 5.5%)were prepared as both white solid from 301-5 and1-((3-chloro-1-phenylpropoxy)methyl)-2-fluorobenzene (75 mg, 0.27 mmol)according to the procedure for 140. 301: ¹HNMR (400 MHz, CDCl₃) δ 8.04(s, 1H), 7.75 (m, 2H), 7.42 (d, J=6 Hz, 1H), 7.34-7.28 (m, 7H), 7.16 (d,J=10.4 Hz, 2H), 7.10-6.92 (m, 3H), 5.27-5.16 (m, 2H), 4.59-4.36 (m, 2H),4.32-4.20 (m, 1H), 3.87 (s, 3H), 3.41-3.18 (m, 1H), 2.46-2.31 (m, 1H),2.13-1.95 (m, 1H). Mass (m/z): 676.13[M+H]⁺. 302: ¹HNMR (400 MHz, CDCl₃)δ 8.05 (s, 1H), 7.87 (d, J=6.0 Hz, 1H), 7.80 (dd, J=2.4, 10.0 Hz, 1H),7.48 (d, J=6.0 Hz, 1H), 7.37-7.27 (m, 7H), 7.16-7.08 (m, 3H), 7.02-6.92(m, 2H), 5.21 (m, 2H), 4.57 (m, 1H), 4.49 (d, J=12.0 Hz, 1H), 4.36 (d,J=12.0 Hz, 1H), 3.87 (s, 3H), 3.85-3.77 (m, 1H), 3.69-3.61 (m, 1H),2.35-2.27 (m, 2H). Mass (m/z): 692.14, [M+H]⁺.

3-fluoro-1-(3-fluoro-4-methoxybenzyl)-5-(6-methyl-2-((3-oxobutyl)sulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(303)

Step 1: The titled compound 303-01 was prepared in a yield of 92.5%(0.74 g, 1.96 mmol) as a light yellow solid from2,4-dichloro-6-methylpyrimidine (0.52 g, 3.19 mmol) and 301-02 (0.8 g,2.12 mmol) according to the procedure for 99-01. Mass (m/z): 378.11,[M+H]⁺.

Step 2: The titled compound 303-02 was prepared without purification asa yellow solid (0.58 g) from 303-01 (0.74 g, 1.96 mmol) according to theprocedure for 140-1. Mass (m/z): 376.09, [M+H]⁺.

Step 3: The title compound 303 (4 mg, 0.0084 mmol) was prepared in ayield of 14% as a white solid from 303-02 (24 mg, 0.06 mmol) and4-chlorobutan-2-one (7.8 mg, 0.07 mmol), according to the procedure for140. H NMR (400 MHz, CDCl₃) δ 8.37 (dd, J=1.2, 2.0 Hz, 1H), 7.72 (dd,J=2.4, 10.0 Hz, 1H), 7.40 (s, 1H), 7.17 (d, J=9.6 Hz, 2H), 6.94 (t,J=8.4 Hz, 1H), 5.21 (s, 2H), 3.87 (s, 3H), 3.85-3.83 (m, 2H), 3.10 (t,J=7.6 Hz, 2H), 2.66 (s, 3H). Mass (m/z): 478.07, [M+H]⁺.

3-fluoro-1-(3-fluoro-4-methoxybenzyl)-5-(2-((3-((2-fluorobenzyl)oxy)butyl)sulfinyl)-6-methylpyrimidin-4-yl)pyridin-2(1H)-one(304) and3-fluoro-1-(3-fluoro-4-methoxybenzyl)-5-(2-((3-((2-fluorobenzyl)oxy)butyl)sulfonyl)-6-methylpyrimidin-4-yl)pyridin-2(1H)-one(305)

The title compound 304 (30 mg, 0.052 mmol) and 305 (66 mg, 0.11 mmol)was prepared as both white solid from 303-02 (70 mg, 0.19 mmol) and1-(((4-chlorobutan-2-yl)oxy)methyl)-2-fluorobenzene (53 mg, 0.25 mmol),according to the procedure for 140. 304: ¹H NMR (400 MHz, CDCl₃) δ 8.30(s, 1H), 7.75-7.71 (m, 1H), 7.38-7.32 (m, 1H), 7.27 (s, 1H) 7.24-7.18(m, 1H), 7.12-7.09 (m, 2H), 7.07-7.01 (m, 1H), 6.99-6.88 (m, 2H), 5.17(m, 2H), 4.63 (d, J=12.0 Hz, 0.5H), 4.56-4.49 (m, 1H), 4.37 (d, J=12.0Hz, 0.5H), 3.86 (s, 3H), 3.78-3.74 (m, 0.56H), 3.67-3.61 (m, 0.59H),3.41-3.33 (m, 0.58H), 3.30-3.18 (m, 1H), 3.15-3.07 (m, 0.60H), 2.64 (s,3H), 2.25-2.17 (m, 0.72H), 2.15-2.05 (m, 0.71H), 1.98-1.89 (m, 0.62H),Mass (m/z): 572.18, [M+H]⁺. 305: ¹H NMR (400 Hz, CDCl₃) δ 8.32 (m, 1H),7.76 (dd, J=2.4, 10.0 Hz, 1H), 7.42 (s, 1H), 7.38 (td, J=1.6, 7.6 Hz,11H), 7.29-7.23 (m, 1H), 7.13-7.08 (m, 3H), 7.03-6.98 (m, 1H), 6.92 (t,J=8.4 Hz, 1H), 5.19 (d, J=14.4 Hz, 1H), 5.11 (d, J=14.4 Hz, 1H), 4.63(d, J=11.6 Hz, 1H), 4.49 (d, J=11.6 Hz, 11H), 3.85 (s, 3H), 3.83-3.78(m, 1H), 3.77-3.72 (m, 1H), 3.58-3.50 (m, 1H), 2.63 (s, 3H), 2.19-2.10(m, 1H), 2.08-1.98 (m, 1H). Mass (m/z): 588.17, [M+H]⁺.

1′-(3,4-dimethoxybenzyl)-2-((3-((2-fluorobenzyl)oxy)-3-phenylpropyl)sulfonyl)-6-methyl-[4,5′-bipyrimidin]-2′(1′H)-one(306) and1′-(benzo[d][1,3]dioxol-5-ylmethyl)-2-((3-((2-fluorobenzyl)oxy)-3-phenylpropyl)sulfonyl)-6-methyl-[4,5′-bipyrimidin]-2′(1′H)-one(307)

Step 1. The titled compound 306-01 was prepared in a yield of 100% (1.66g, 7.0 mmol) as a white solid from 2,4-dichloro-6-methylpyrimidine (1.5g, 9.24 mmol) according to the procedure for 99-01. Mass (m/z): 237.11,239.12, [M+H]⁺.

Step 2: The titled compound 306-02 was prepared without purification asa yellow solid (0.2 g) from 306-01 (0.25 g, 1.06 mmol) according to theprocedure for 140-01. Mass (m/z): 235.23,[M+H]⁺.

Step 3: The title compound 306-03 (21 mg, 0.047 mmol) was prepared in ayield of 8.5% as a white solid from 306-02 (0.13 g, 0.55 mmol) and1-(((4-chlorobutan-2-yl)oxy)methyl)-2-fluorobenzene (0.18 g, 0.83 mmol),according to the procedure for 140. Mass (m/z): 509.31, [M+H]⁺.

Step 4: The titled compound 306-04 was prepared without purification (21mg) as a yellow syrup from 306-03 (21 mg, 0.047 mmol) according to theprocedure for 99-02. Mass (m/z): 495.29, [M+H]⁺.

Step 5: The titled compound 306 (2 mg, 0.003 mmol) was prepared in ayield of (21%) as a white solid from 306-04 (7 mg, 0.014 mmol) accordingto the procedure for 85-01. ¹H NMR (400 MHz, CDCl₃) δ 8.92 (s, 1H), 7.61(m, 1H), 7.39-7.30 (m, 7H), 7.28-7.24 (m, 1H), 7.12 (dt, J=0.8, 7.2 Hz,1H), 7.03-6.99 (m, 2H), 6.97 (d, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H),5.15 (s, 2H), 4.57 (q, J=4.4 Hz, 1H), 4.49 (d, J=11.6 Hz, 1H), 4.36 (d,J=12.0 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.79-3.73 (m, 1H), 3.63-3.55(m, 1H), 2.65 (s, 3H), 2.25-2.21 (m, 2H). Mass (m/z): 645.29, [M+H]⁺.

Step 6: The titled compound 307 (2.5 mg, 0.004 mmol) was prepared in ayield of (14.3%) as a white solid from 306-04 (14 mg, 0.028 mmol)according to the procedure for 85-01. Mass (m/z): 629.31, [M+H]⁺.

1-(cyclohexylmethyl)-5-(2-(3-(2,4-difluorobenzyloxy)-3-phenylpropylsulfinyl)-6-methylpyrimidin-4-yl)-3-fluoropyridin-2(1H)-one(308) and1-(cyclohexylmethyl)-5-(2-(3-(2,4-difluorobenzyloxy)-3-phenylpropylsulfonyl)-6-methylpyrimidin-4-yl)-3-fluoropyridin-2(1H)-one(309)

Step 1. The compound 308-01 was prepared in a yield of 81.0% as whitesolid (2.46 g) from 165-01 and 2,4-dichloro-6-methylpyrimidine (2.93 g,18.0 mmol) according to the procedure for 99-01. Mass (m/z): 254.00,[M+H]⁺.

Step 2. The compound 308-02 was prepared in a yield of 86.9% as yellowsolid (2.12 g) from compound 308-01 (2.46 g, 9.7 mmol) according to theprocedure for 140-01. Mass (m/z): 418.04 [M+H]⁺.

Step 3. K₂CO₃(397 mg, g 2.88 mmol) was added to the solution of 308-02(390 mg, 1.44 mmol) and1-((3-chloro-1-phenylpropoxy)methyl)-2,4-difluorobenzene (469 mg, 1.58mmol) in DMF (15 mL) under N₂. Then the reaction mixture was stirred atroom temperature overnight. The reaction was quenched by water,extracted by EtOAc for 3 times. The organic layer was combined, washedby brine, dried over Na₂SO₄. Evaporation to remove the solvent to give308-03 as light yellow oil (850 mg). The cruel product was used withoutfurther purification. Mass (m/z): 513.32 [M+H]⁺.

Step 4. The HBr (aq, 5 mL) was added to the solution of 308-03 (500 mg,0.98 mmol) in 1,4-dioxane (10 mL). Then the reaction mixture was stirredat 50° C. for 1.5 h. The reaction mixture was cooled to roomtemperature, diluted by water. Filtration to give 437 mg 308-04 as aorange solid (89.7%). Mass (m/z): 498.18 [M+H]⁺.

Step 5. The mixture of 308-04 (67 mg, 0.13 mmol),(bromomethyl)cyclohexane (166 mg, 0.94 mmol) and K₂CO₃ (83 mg, 0.94mmol) in ACN (5 mL) was reacted under microwave at 180° C. for 11 min.The reaction mixture was diluted by water, extracted by EtOAc for 3times. The organic layer was combined, washed by brine, dried overNa₂SO₄ and further purified by silica gel column chromatography(PE:EA=5.1) to give 39 mg 308-05 as colorless oil (48.8%). Mass (m/z):594.26 [M+H]⁺.

Step 6. The titled compounds 308 (12.5 mg, 29.8%) and 309 (5.6 mg,14.8%) were prepared as both white solid from 308-05 (39 mg, 0.066 mmol)according to the procedure for 80 and 81. 308: ¹HNMR (400 MHz, CDCl₃) δ8.16 (s, 1H), 7.72-7.69 (m, 2H), 7.54-7.51 (m, 1H), 7.36-7.26 (m, 5H),6.86-6.71 (m, 2H), 4.56-4.53 (m, 1H), 4.45-4.35 (m, 2H), 4.32-4.20 (m,2H), 3.93 (d, J=7.2 Hz, 2H), 3.35-3.05 (m. 2H), 2.62 (s, 3H), 2.47-2.21(m, 2H), 2.08-2.00 (m, 1H), 1.92-1.87 (m, 1H), 1.75-1.63 (m, 6H),1.44-1.40 (m, 2H). Mass (m/z): 610.28[M+H]⁺. 309: ¹HNMR (400 MHz, CDCl₃)δ 8.16 (s, 1H), 7.71 (dd, J=2.4, 10 Hz, 1H), 7.39-7.32 (m, 7H),6.88-6.83 (m, 1H), 6.81-6.76 (m, 1H), 4.58-4.55 (m, 1H), 4.46 (d, J=11.6Hz, 1H), 4.35 (d, J=11.6 Hz, 1H), 3.93 (d, J=7.6 Hz, 2H), 3.80-3.72 (m,1H), 3.62-3.55 (m, 1H), 2.64 (s, 3H), 2.40-2.25 (m. 2H), 1.94-1.86 (m,1H), 1.75-1.64 (m, 6H), 1.27-1.17 (m, 4H). Mass (m/z): 626.20[M+H]⁺.

5-(2-((3-((2,4-difluorobenzyl)oxy)-3-phenylpropyl)sulfinyl)-6-methylpyrimidin-4-yl)-1-(3-ethoxybenzyl)-3-fluoropyridin-2(1H)-one(310) and5-(2-((3-((2,4-difluorobenzyl)oxy)-3-phenylpropyl)sulfonyl)-6-methylpyrimidin-4-yl)-1-(3-ethoxybenzyl)-3-fluoropyridin-2(1H)-one(311)

The titled compounds 310 (9.3 mg, 21.5%) and 311 (13.6 mg, 26.4%) wereprepared as colorless oil and white solid from 308-04 (100 mg, 0.21mmol) and 1-(bromomethyl)-3-ethoxybenzene (50.0 mg, 0.23 mmol) accordingto the procedure for 80 and 81. 310: ¹HNMR (400 MHz, CDCl₃) δ 8.21 (s,1H), 7.74-7.69 (m, 2H), 7.54-7.51 (m, 1H), 7.36-7.28 (m, 6H), 7.25 (m,1H), 6.94-6.80 (m, 4H), 5.23 (s, 2H), 4.55 (m, 1H), 4.45-4.42 (m, 4H),4.03-3.97 (m, 2H), 3.33-3.30 (m, 2H), 2.61 (s, 3H), 1.38 (t, J=7.2 Hz,3H). Mass (m/z): 648.20[M+H]⁺; 311: ¹HNMR (400 MHz, CDCl₃) δ 8.21 (s,1H), 7.74-7.69 (m, 1H), 7.53 (m, 1H), 7.38-7.28 (m, 7H), 6.89-6.83 (m,5H), 5.22 (s, 2H), 4.56 (m, 1H), 4.42 (d, J=11.6 Hz, 1H), 4.34-4.28 (m,2H), 4.02 (q, J=7.2 Hz, 2H), 3.77-3.69 (m, 1H), 3.60-3.52 (m, 1H), 2.62(s, 1H), 1.38 (t, J=6.8 Hz, 3H). Mass (m/z): 664.16[M+H]⁺.

5-(2-(3-(2,4-difluorobenzyloxy)-3-phenylpropylsulfonyl)-6-methylpyrimidin-4-yl)-3-fluoro-1-(piperidin-4-ylmethyl)pyridin-2(1H)-one(312)

Step 2. The compounds 312-02 (51 mg) was prepared in a yield of 97.5% ascolorless oil from 312-01 (50 mg, 0.07 mmol) according to the procedurefor 81. Mass (m/z): 727.27, [M+H]⁺.

Step 3. TFA (0.5 mL) was added to the solution of 312-02 (51 mg, 0.07mmol) in DCM. The reaction mixture was stirred at room temperature for 2h. NaHCO₃(aq) was added to the mixture to neutralized the left TFA. Theaqueous phase was extracted by DCM for 3 times. The organic layer wascombined, washed by brine, dried over Na₂SO₄, further purified by silicagel column chromatography (DCM:MeOH=10:1) to give 312 as 19 mg whitesolid. ¹HNMR (400 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.12 (s, 2H), 7.73-7.65(m, 1H), 7.50-7.44 (m, 1H), 7.39-7.32 (m, 4H), 7.22-7.17 (m, 1H),7.07-7.03 (m, 1H), 4.62-4.59 (m, 1H), 4.34 (d, J=5.2 Hz, 2H), 4.03 (d,J=7.2 Hz, 2H), 3.78-3.71 (m, 1H), 3.66-3.58 (m, 1H), 3.33 (s, 3H), 3.28(d, J=13.6 Hz, 1H), 2.85-2.78 (m, 1H), 2.57 (s, 2H), 2.19-1.98 (m, 4H),1.73-1.55 (m, 2H), 1.47-1.34 (n, 2H). Mass (m/z): 627.21[M+H]⁺

5-(2-(3-(2,4-difluorobenzyloxy)-3-phenylpropylsulfinyl)-6-methylpyrimidin-4-yl)-3-fluoro-1-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2(1H)-one(313) and5-(2-(3-(2,4-difluorobenzyloxy)-3-phenylpropylsulfonyl)-6-methylpyrimidin-4-yl)-3-fluoro-1-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2(1H)-one(314)

The titled compounds 313 (11.7 mg, 16.3%) and 314 (8.5 mg, 11.2%) wereprepared as light yellow solid and white solid from 308-04 (50 mg, 0.10mmol) and 4-(bromomethyl)tetrahydro-2H-pyran (179 mg, 1.0 mmol)according to the procedure for 80 and 81. 313: ¹HNMR (400 MHz, CDCl₃) δ8.185 (s, 1H), 7.73 (dd, J=2.4, 10 Hz, 1H), 7.40-7.32 (m, 7H), 6.87-6.75(m, 2H), 4.58 (m, 1H), 4.46 (d, J=11.6 Hz, 1H), 4.35 (d, J=11.6, 1H),3.99 (d, J=7.2 Hz, 3H), 3.79-3.72 (m, 1H), 3.62-3.54 (m, 1H), 3.38-3.31(t, J=11.6 Hz, 2H), 2.64 (s, 3H), 2.36-2.16 (m, 4H), 1.56 (d, J=11.2 Hz,2H), 1.47-1.41 (m, 2H). Mass (m/z): 612.46 [M+H]⁺. 314: ¹HNMR (400 MHz,CDCl₃) δ 8.20 (s, 1H), 7.73-7.69 (m, 1H), 7.36-7.27 (m, 7H), 6.86-6.71(m, 2H), 4.56 (m, 1H), 4.46-4.25 (m, 3H), 3.99 (d, J=6.8 Hz, 3H), 3.34(m, 3H), 2.62 (m, 3H), 2.46-1.98 (m, 4H), 1.55-1.40 (m, 4H). Mass (m/z):628.43[M+H]⁺.

1-(3,4-dichlorobenzyl)-5-(2-(3-(2,4-difluorobenzyloxy)-3-phenylpropylsulfinyl)-6-methylpyrimidin-4-yl)-3-fluoropyridin-2(1H)-one(315) and1-(3,4-dichlorobenzyl)-5-(2-(3-(2,4-difluorobenzyloxy)-3-phenylpropylsulfonyl)-6-methylpyrimidin-4-yl)-3-fluoropyridin-2(1H)-one(316)

The titled compounds 315(11.4 mg, 26.5%) and 316(17.5 mg, 30.4%) wereprepared as light yellow solid and white solid from 308-04 (102 mg, 0.21mmol) and 4-(bromomethyl)-1,2-dichlorobenzene (55.4 mg, 0.23 mmol)according to the procedure for 81 and 82. 315: ¹HNMR (400 MHz, CDCl₃) δ8.32 (s, 1H), 7.74-7.69 (m, 1H), 7.45 (s, 1H), 7.43 (dd, J=2.0, 8.4 Hz.1H), 7.35-7.29 (m, 7H), 7.23-7.20 (m, 1H), 6.86-6.70 (m, 2H), 5.21 (s,2H), 4.56-4.21 (m, 4H), 3.35-3.05 (m, 2H), 2.62 (s, 3H), 2.5-2.31 (m,2H). Mass (m/z): 656.33[M+H]; 316: ¹HNMR (400 MHz, CDCl₃) δ 8.29 (s,1H), 7.74 (dd, J=2.0, 9.6 Hz, 1H), 7.45-7.30 (m, 9H), 7.21 (dd, J=2.0,8.0 Hz, 1H), 6.87-6.82 (m, 1H), 6.80-6.74 (m, 1H), 5.20 (s, 2H), 4.57(dd, J=4.8, 8.4 Hz. 1H), 4.45 (d, J=11.6 Hz, 1H), 4.34 (d, J=11.6 Hz,1H), 3.79-3.72 (m, 1H), 3.61-3.53 (m, 1H), 2.64 (s, 3H), 2.39-2.23 (m,2H). Mass (m/z): 672.30[M+H]⁺

1-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(2-((3-((2,4-difluorobenzyl)oxy)-3-phenylpropyl)sulfonyl)-6-methylpyrimidin-4-yl)-3-fluoropyridin-2(1H)-one(317)

The titled compounds 317 (15.3 mg) were prepared in a yield of 12.8% aswhite solid from 308-04 (90 mg, 0.18 mmol) and5-(bromomethyl)benzo[d][1,3]dioxole (43 mg, 0.20 mmol) according to theprocedure for 85. ¹HNMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 7.72 (dd, 2.0,9.6 Hz, 1H), 7.39-7.28 (m, 7H), 6.85 (m, 3H), 6.79-6.74 (m, 2H), 5.94(s, 2H), 6.15 (s, 2H), 4.56 (m, 1H), 4.45 (d, J=12.0 Hz, 1H), 4.34 (d,J=12.0 Hz, 1H), 3.77-3.68 (m, 1H), 3.60-3.53 (m. 1H), 2.62 (s, 3H),2.38-2.20 (m, 2H). Mass (m/z): 664.38[M+H]⁺.

1-(benzo[d][1,3]dioxol-5-ylmethyl)-3-fluoro-5-(2-(3-(2-fluorobenzyloxy)-3-phenylpropylsulfonyl)-6-methylpyrimidin-4-yl)pyridin-2(1H)-one(318)

Step 1. The compound 318-01 (2.26 g) was prepared as light yellow oilfrom 308-02 (1 g, 3.98 mmol) and1-((3-chloro-1-phenylpropoxy)methyl)-2-fluorobenzene (1.22 g, 4.38 mmol)according to the procedure for 308-03. Mass (m/z): 494.16[M+H]⁺.

Step 2. The compound 318-02 (1.77 g) was prepared in a yield of 92.6% aslight yellow oil from 318-01 (2.20 g, 4.46 mmol) according to theprocedure for 308-04. Mass (m/z): 480.29 [M+H]⁺.

Step 3. The titled compound 318 (98.3 mg) was prepared in a yield of36.9% as white solid from 318-02 (200 mg, 0.42 mmol) and5-(bromomethyl)benzo[d][1,3]dioxole (100 mg, 0.46 mmol) according to theprocedure for 85. 318: ¹H NMR (400 MHz, CDCl₃) δ 8.24 (s, 1H), 7.72 (dd,J=2.4, 10 Hz, 1H), 7.39-7.27 (m, 8H), 7.12 (t, J=7.6 Hz, 1H), 7.03 (t,J=9.6 Hz, 1H), 6.85 (d, J=9.2 Hz, 2H), 6.78 (d, J=8.0 Hz, 1H), 5.95 (s,2H), 5.14 (s, 2H), 4.58 (dd, J=4.8, 8.4 Hz, 1H), 4.50 (d, J=12.0 Hz,1H), 4.37 (d, J=12.0 Hz, 1H), 3.81-3.74 (m, 1H), 3.62-3.54 (m, 1H), 2.63(s. 3H), 2.34-2.26 (m, 2H). Mass (m/z): 664.38[M+H]⁺

1-(benzo[c][1,2,5]thiadiazol-5-ylmethyl)-3-fluoro-5-(2-(3-(2-fluorobenzyloxy)-3-phenylpropylsulfonyl)-6-methylpyrimidin-4-yl)pyridin-2(1H)-one(319)

The titled compound 319(30.1 mg) was prepared in a yield of 25.1% aslight yellow solid from 318-02 (100 mg, 0.21 mmol) and5-(bromomethyl)benzo[c][1,2,5]thiadiazole (58 mg, 0.23 mmol) accordingto the procedure for 85. ¹HNMR (400 MHz, CDCl₃) δ 8.37 (s, 1H), 8.02 (d,J=8.8 Hz, 1H), 7.87 (s. 1H), 7.78 (dd, J=2.4, 9.6 Hz, 1H), 7.60 (dd,J=2.0, 8.8 Hz, 1H), 7.38 (s, 1H), 7.36-7.30 (m, 7H), 7.10 (t, J=7.4 Hz,1H), 7.00 (t, J=10.0 Hz, 1H), 5.43 (s, 2H), 4.56 (dd, J=8.0, 4.4 Hz,1H), 4.49 (d, J=12.0 Hz, 1H), 4.36 (d, J=12.0 Hz, 1H), 3.82-3.75 (m,1H), 3.61-3.53 (m, 1H), 2.63 (s, 3H), 2.33-2.19 (m, 2H). Mass (m/z):660.42[M+H]⁺.

1-(benzo[d][1,3]dioxol-4-ylmethyl)-3-fluoro-5-(2-(3-(2-fluorobenzyloxy)-3-phenylpropylsulfonyl)-6-methylpyrimidin-4-yl)pyridin-2(1H)-one(320)

The titled compound 320(71.7 mg) was prepared in a yield of 53.3% aslight yellow solid from 318-02 (100 mg, 0.21 mmol) and4-(bromomethyl)benzo[d][1,3]dioxole (49.8 mg, 0.23 mmol) according tothe procedure for 85. ¹HNMR (400 MHz, CDCl₃) δ 8.53 (s, 1H), 7.67 (dd,J=2.4, 10.0 Hz, 1H), 7.39-7.31 (m, 8H), 7.10 (t, J=7.2 Hz, 1H), 6.99 (t,J=9.6 Hz, 1H), 6.93-6.91 (m, 1H), 6.83-6.78 (m, 2H), 5.22 (s, 2H), 4.58(dd, J=4.8, 8.0 Hz, 1H), 4.49 (d, J=11.6 Hz, 1H), 4.37 (d, J=11.6 Hz,1H), 3.79-3.72 (m, 1H), 3.62-3.55 (M, 1H), 2.63 (s, 3H), 2.36-2.24 (m,2H). Mass (m/z): 646.24 [M+H]⁺

3-fluoro-5-(2-(3-(2-fluorobenzyloxy)-3-phenylpropylsulfonyl)-6-methylpyrimidin-4-yl)-1-((2-methoxypyridin-4-yl)methyl)pyridin-2(1H)-one(321)

The titled compound 321(55.5 mg) was prepared in a yield of 46.0% aswhite solid from 318-02 (105 mg, 0.22 mmol) and4-(bromomethyl)-2-methoxypyridine (40 mg, 0.20 mmol) according to theprocedure for 85. ¹HNMR (400 MHz, CDCl₃) δ 8.29 (s, 1H), 8.15 (d, J=5.6Hz, 1H), 7.78 (dd, J=2.0, 9.6 Hz, 1H), 7.41 (s, 1H), 7.39-7.27 (m, 7H),7.10 (t, J=7.6 Hz, 1H), 7.00 (t, J=9.6 Hz, 1H), 6.80 (d, J=4.8 Hz, 1H),6.59 (s, 1H), 5.21 (s, 2H), 4.56 (m, 1H), 4.49 (d, J=11.6 Hz, 1H), 4.37(d, J=12.0 Hz, 1H), 3.92 (s, 3H), 3.83-3.75 (m, 1H), 3.61-3.53 (m, 1H),2.63 (s, 3H), 2.34-2.26 (m, 2H). Mass (m/z): 633.36[M+H]⁺

1-((1H-benzo[d]imidazol-6-yl)methyl)-3-fluoro-5-(2-(3-(2-fluorobenzyloxy)-3-phenylpropylsulfonyl)-6-methylpyrimidin-4-yl)pyridin-2(1H)-one(322)

Step 1. The compounds 322-01 and 322-02 was prepared from 318-02 (253mg, 0.53 mmol) and the mixture of tert-butyl5-(bromomethyl)-1H-benzo[d]imidazole-1-carboxylate and tert-butyl6-(bromomethyl)-1H-benzo[d]imidazole-1-carboxylate (181 mg, 0.58 mmol)according to the procedure for 85. Mass (m/z): 742.24[M+H]⁺.

Step 2. The titled compound 322 (9 mg) was prepared in a yield of 2.4%as light yellow solid from the mixture of 322-01 and 322-02 according tothe procedure for 312. 322: ¹HNMR (400 MHz, DMSO-d₆) δ 8.91 (s. 1H),8.42 (br, 1H), 8.13 (s, 2H), 7.73-7.63 (m, 2H), 7.40-7.28 (m, 8H),7.15-7.11 (m, 2H), 5.39 (s, 2H), 4.60 (m, 1H), 4.34 (dd, 12.0, 16.4 Hz,2H), 4.03 (dd, J=6.8, 14.0 Hz, 3H), 3.77-3.59 (m, 2H), 2.57 (s, 3H).Mass (m/z): 642.33[M+H]⁺.

5-((3-fluoro-5-(2-(3-(2-fluorobenzyloxy)-3-phenylpropylsulfonyl)-6-methylpyrimidin-4-yl-2-oxopyridin-1(2H)-yl)methyl)benzo[c][1,2,5]oxadiazole1-oxide (323)

The titled compound 323(14.7 mg) was prepared in a yield of 11.7% (2steps) as white solid from 318-02 (50 mg, 0.11 mmol) and5-(bromomethyl)benzo[c][1,2,5]oxadiazole according to the procedure for85. ¹HNMR (400 MHz, CDCl₃) δ 8.37 (s, 1H), 7.77 (dd, J=2.0, 9.6 Hz, 1H),7.40-7.28 (m, 9H), 7.10 (t, J=6.4 Hz, 1H), 7.00 (t, J=9.6 Hz, 1H), 5.24(s, 2H), 4.55 (m, 1H), 4.50 (d, J=12.0 Hz, 1H), 4.37 (d, J=12.0 Hz, 1H),3.82-3.75 (m, 1H), 3.61-3.54 (m, 1H), 2.64 (s, 3H), 2.35-2.23 (m, 2H).Mass (m/z): 660.09[M+H]⁺.

1-(3,4-dimethoxybenzyl)-3-fluoro-5-(6-methyl-2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(324)

Step 1. CH₃I (85 mg. 0.6 mmol) was added to the mixture of 308-02 (100mg, 0.4 mmol), K₂CO₃ (83 mg, 0.6 mmol) and DMF (10 mL) under 0° C., thenthe reaction mixture was warmed to room temperature, stirred overnight.The reaction mixture was quenched by water, extracted by EtOAc for 3times, dried over Na₂SO₄. Evaporation to remove the solvent to give324-01(221 mg) as yellow solid. The cruel product was used withoutfurther purification. Mass (m/z): 267.16[M+H]⁺.

Step 2. HBr (aq, 3 mL) was added to the solution of 324-01 in EtOH under0° C. Then the reaction mixture was refluxed for 2 h. Evaporation toremove the solvent, the residue was diluted by water, filtrated to givecruel product 324-02 as yellow solid. The cruel product was used withoutfurther purification. Mass (m/z): 253.12[M+H]⁺.

Step 3. The compounds 324 (65.4 mg) was prepared in a yield of 75.8% (2steps) as white solid from 324-02 (50 mg, 0.2 mmol) and t4-(bromomethyl)-1,2-dimethoxybenzene (16 mg, 0.4 mmol) according to theprocedure for 85. ¹HNMR (400 MHz, CDCl₃) δ 8.31 (s, 1H), 7.71 (dd,J=2.4, 9.6 Hz, 1H), 7.36 (s, 1H), 6.95 (d, J=10.0 Hz, 2H), 6.862 (d,J=8.0 Hz, 1H), 5.22 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.33 (s, 3H),2.66 (s, 3H). Mass (m/z): 434.11 [M+H]⁺

3-fluoro-5-(2-(3-(2-fluorobenzyloxy)-3-phenylpropylsulfonyl)-6-methylpyrimidin-4-yl)pyridin-2(1H)-one(325)

Step 1. The compounds 325-01 (331 mg) was prepared in a yield of 22.6%as colorless oil from 318-01 (1.5 g, 3.04 mmol) according to theprocedure for 81. Mass (m/z): 326.24[M+H]⁺.

Step 2. The titled compound 325 (232.3 mg) was prepared in a yield of72.3% as white solid from 325-01 (315 mg, 0.97 mmol) according to theprocedure for 99-02. ¹HNMR (400 MHz, CDCl₃) δ 8.28 (d, J=2.0 Hz, 1H),7.99 (dd, J=2.4, 10.4 Hz, 1H), 7.47 (s, 1H), 7.40-7.30 (m, 7H), 7.12 (t,J=7.6 Hz, 1H), 7.02 (t, J=9.6 Hz, 1H), 4.58 (m, 1H), 4.52 (d, J=11.6 Hz,1H), 4.3 (d, J=11.6 Hz, 1H), 3.85-3.77 (m, 1H), 3.65-3.58 (m, 1H), 2.66(s, 3H), 2.35-2.27 (m, 2H). Mass (m/z): 512.25 [M+H]⁺.

1-(benzo[d]thiazol-5-ylmethyl)-3-fluoro-5-(2-(3-(2-fluorobenzyloxy)-3-phenylpropylsulfonyl)-6-methylpyrimidin-4-yl)pyridin-2(1H)-one(326)

The titled compound 326 was prepared in a yield of 21.2% as light yellowsolid (21.2 g) from 325 (30 mg, 0.058 mmol) and5-(bromomethyl)benzo[d]thiazole (28.5 mg, 0.12 mmol) according to theprocedure for 85-01. ¹HNMR (400 MHz, CDCl₃) δ 9.02 (s, 1H), 8.36 (s,1H), 8.13 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.73 (m, 1H), 7.53 (m, 2H),7.37-7.28 (m, 7H), 7.10 (t, J=7.6 Hz, 1H), 7.00 (t, J=9.6 Hz, 1H), 5.39(m, 3H), 4.55 (m, 1H), 4.50 (d, J=11.6 Hz, 1H), 4.37 (d, J=12.0, 1H),4.21 (t, J=5.6 Hz, 1H), 3.81-3.74 (m, 1H), 3.61-3.53 (m. 1H), 2.63 (s,3H). Mass (m/z): 659.31[M+H]⁺.

3-fluoro-5-(2-(3-(2-fluorobenzyloxy)-3-phenylpropylsulfonyl)-6-methylpyrimidin-4-yl)-1-((1-methyl-1H-indazol-5-yl)methyl)pyridin-2(1H)-one(327) and5-((3-fluoro-5-(2-(3-(2-fluorobenzyloxy)-3-phenylpropylsulfonyl)-6-methylpyrimidin-4-yl)pyridin-2-yloxy)methyl)-1-methyl-1H-indazole(328)

DIAD (24 mg, 0.12 mmol) was added to the solution of 325 (30 mg, 0.06mmol), (1-methyl-1H-indazol-5-yl)methanol (10 mg, 0.06 mmol) and PPh₃(30 mg, 012 mmol) in THF at 0° C. under N₂. Then the reaction mixturewas heated to 50° C. and stirred for 2 h. Evaporation to remove thesolvent, the residue was diluted by water, extracted by EtOAc for 3times. The organic layer was combined, washed by brine, dried overNa₂SO₄, further purified by pre-TLC (PE:EA=1:1) to give the titledcompounds 327(15 mg, 38.1%) as light yellow solid and 328(7 mg, 19.1%)as white solid. 327: ¹HNMR (400 MHz, CDCl₃) δ 8.31 (dd, J=0.8, 2.0 Hz,1H), 7.96 (s, 1H), 7.74-7.69 (m, 2H), 7.54-7.51 (m, 1H), 7.44 (dd,J=1.2, 8.8 Hz, 1H), 7.38-7.30 (m, 8H), 7.09 (td, J=0.8, 7.6 Hz, 1H),7.00 (m, 1H), 5.34 (m, 2H), 4.55 (m, 1H), 4.49 (d, J=12.0 Hz, 1H), 4.36(d, J=12.0 Hz, 1H), 4.05 (s, 3H), 3.78-3.72 (m, 1H), 3.60-3.52 (m. 1H),2.59 (s, 3H), 2.36-2.20 (m, 2H). Mass (m/z): 656.41[M+H]⁺. 328: ¹HNMR(400 MHz, CDCl₃) δ 8.68 (d, J=2.0, 1H), 8.13 (dd, J=2.0, 10.4 Hz, 1H),7.99 (m, 1H), 7.88 (m, 1H), 7.73-7.69 (m, 1H), 7.63 (s, 1H), 7.57-7.51(m, 2H), 7.49-7.30 (m, 6H), 7.12 (td, J=1.2, 7.6 Hz, 1H), 7.01 (m, 1H),5.66 (s, 2H), 4.59 (m, 1H), 4.52 (d, J=12.0 Hz, 1H), 4.39 (d, J=12.0 Hz,1H), 4.09 (s, 3H), 3.85-3.77 (m, 1H), 3.66-3.59 (m, 1H), 2.68 (s, 3H),2.40-2.26 (m, 2H). Mass (m/z): 656.51[M+H]⁺.

1-(benzo[d]oxazol-5-ylmethyl)-3-fluoro-5-(2-((3-((2-fluorobenzyl)oxy)-3-phenylpropyl)sulfonyl)-6-methylpyrimidin-4-yl)pyridin-2(1H)-one(329)

The titled compound 329 was prepared in a yield of 65.2% as light yellowsolid (9 mg, 0.015 mmol) from 325 (12 mg, 0.023 mmol) and5-(bromomethyl)benzo[d]oxazole (7.3 mg, 0.035 mmol) according to theprocedure for 85-01. ¹H NMR (400 MHz, CDCl₃) δ 8.31 (q, J=1.2 Hz, 1H),8.11 (s, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.75 (dd, J=2.4, 9.6 Hz, 1H), 7.59(d, J=8.8 Hz, 1H), 7.45 (dd, J=1.6, 8.4 Hz, 1H), 7.36-7.30 (m, 7H),7.27-7.23 (m, 1H), 7.12 (dt, J=1.2, 7.2 Hz, 1H), 7.00-6.97 (m, 1H), 5.37(s, 2H), 4.57 (dd, J=4.8, 8.4 Hz, 1H), 4.50 (d, J=12.0 Hz, 1H), 4.37 (d,J=12.0 Hz, 1H), 3.82-3.74 (m, 1H), 3.61-3.54 (m, 1H), 2.62 (s, 1H),2.36-2.23 (m, 2H). Mass (m/z). 643.33, [M+H]⁺.

3-fluoro-5-(2-(3-(2-fluorobenzyloxy)-3-phenylpropylsulfonyl)-6-methylpyrimidin-4-yl)-1-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methyl)pyridin-2(1H)-one(330)

The titled compound 330 was prepared in a yield of 52.9% as light yellowsolid (17 mg) from 325 (25 mg, 0.049 mmol) and5-(bromomethyl)-1-methyl-1H-benzo[d][1,2,3]triazole (22 mg, 0.098 mmol)according to the procedure for 85-01. ¹HNMR (400 MHz, CDCl₃) δ 8.33 (s,1H), 8.06 (s, 1H), 7.78 (dd, J=1.6, 9.6 Hz, 1H), 7.60 (dd, J=8.4, 24.8Hz, 2H), 7.42 (s, 1H), 7.38-7.28 (m, 6H), 7.09 (td, J=1.2, 7.6 Hz, 1H),7.02 (m, 1H), 5.42 (s, 2H), 4.57 (m, 1H), 4.49 (d, J=11.6 Hz, 1H), 4.36(d, J=11.6 Hz, 1H), 4.30 (s, 3H), 3.80-3.72 (m, 1H), 3.60-3.53 (m, 1H),2.61 (s, 3H), 2.35-2.23 (m, 3H). Mass (m/z): 657.47[M+H]⁺.

1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3-fluoro-5-(2-(3-(2-fluorobenzyloxy)-3-phenylpropylsulfonyl)-6-methylpyrimidin-4-yl)pyridin-2(1H)-one(331)

The titled compound 331 was prepared in a yield of 83.3% as white solid(17 mg) from 325 (40 mg, 0.08 mmol) and6-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine (36 mg, 0.16 mmol)according to the procedure for 85-01. ¹HNMR (400 MHz, CDCl₃) δ 8.20 (m,1H), 7.72 (dd, J=2.4, 9.6 Hz, 1H), 7.39-7.27 (m, 8H), 7.10 (td, J=1.2,7.2 Hz, 1H), 7.00 (m, 1H), 6.86 (m, 3H), 5.12 (s, 2H), 4.58 (m, 1H),4.50 (d, J=12.0 Hz, 1H), 4.37 (d, J=12.0 Hz, 1H), 4.22 (s, 4H),3.80-3.73 (m, 1H), 3.61-3.54 (m, 1H), 2.63 (m, 3H), 2.34-2.24 (m, 2H).Mass (m/z): 660.51 [M+H]⁺

3-fluoro-5-(2-((3-((2-fluorobenzyl)oxy)-3-phenylpropyl)sulfonyl)-6-methylpyrimidin-4-yl)-1-(4-methoxy-3-(prop-2-yn-1-yloxy)benzyl)pyridin-2(1H)-one(332)

The titled compound 332 (16 mg, 21% yield) was prepared as a white solidfrom 325 (50 mg, 0.11 mmol) and4-(bromomethyl)-1-methoxy-2-(prop-2-yn-1-yloxy)benzene (32 mg, 0.13mmol) according to the procedure for 85-01. ¹H NMR (400 MHz, CDCl₃) δ8.27 (m, 1H), 7.70 (dd, J=2.4, 10 Hz, 1H), 7.39-7.23 (m, 8H), 7.13-7.07(m, 2H), 7.03-6.90 (m, 2H), 6.85 (d, J=8.3 Hz, 1H), 5.19 (s, 2H), 4.74(d, J=2.4 Hz, 2H), 4.58-4.54 (d, J=11.8 Hz, 1H), 4.49 (d, J=11.8 Hz,1H), 4.35 (d, J=11.8 Hz, 1H), 3.84 (s, 3H), 3.80-3.73 (m, 1H), 3.62-3.54(m, 11H), 2.61 (s, 3H), 2.53 (t, J=2.4 Hz, 1H), 2.39-2.21 (m, 3H). Mass(m/z): 686.23, [M+H]⁺.

1-(benzo[d][1,3]dioxol-5-ylmethyl)-3-fluoro-5-(6-methyl-2-((3-phenyl-3-(pyridin-3-yloxy)propyl)sulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(333)

Step 1: The title compound 333-01 (0.06 g, 0.12 mmol) was prepared in ayield of 17% as a white solid from 308-02 (0.18 g, 0.72 mmol) and3-(3-chloro-1-phenylpropoxy)pyridine (0.23 g, 0.93 mmol), according tothe procedure for 140. Mass (m/z): 495.29, [M+H]⁺.

Step 2: The titled compound 333-02 was prepared without purification (24mg) as a white solid from 333-01(60 mg, 0.012 mmol) according to theprocedure for 99-02. Mass (m/z): 481.19, [M+H]⁺.

Step 3 The titled compound 333 (12 mg, 0.02 mmol, 40% yield) wasprepared as a white solid from 333-02 (24 mg, 0.05 mmol) and5-(bromomethyl)benzo[d][1,3]dioxole (16 mg, 0.075 mmol) according to theprocedure for 85-01. ¹H NMR (400 MHz, CDCl3) δ 8.24 (q, J=1.2 Hz, 1H),8.21 (m, 1H), 8.14 (m, 1H), 7.71 (dd, J=2.4, 9.6 Hz, 1H), 7.37-7.27 (m,6H), 7.09-7.08 (m, 2H), 6.86 (dd, J=1.6, 6.8 Hz, 2H), 6.79 (dd, J=1.6,6.8 Hz, 1H), 5.95 (s, 2H), 5.40 (dd, J=5.2, 7.6 Hz, 1H), 5.17 (d, J=2.0Hz, 2H), 3.85-3.69 (m, 2H), 2.62 (s, 3H), 2.57-2.51 (m, 2H). Mass (m/z):615.27, [M+H]⁺.

1-(benzo[d][1,3]dioxol-5-ylmethyl)-3-fluoro-5-(6-(fluoromethyl)-2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one(334)

Step 1: The titled compound 334-01 was prepared in a yield of 26.7%(2.86 g, 2.13 mmol) as a white solid from 161-02 (1.54 g, 8.0 mmol)according to the procedure for 99-01. Mass (m/z): 284.23, [M+H]⁺.

Step 2: The titled compound 334-02 was prepared without purification(2.50 g) as a yellow solid from 334-01 (2.86 g, 2.13 mmol) according tothe procedure for 99-02. Mass (m/z): 270.19, [M+H]⁺.

Step 3. The titled compound 334 was prepared in a yield of 79.7% (0.7 g,1.61 mmol) as a colorless oil from 334-02 (0.5 g, 2.01 mmol) and5-(bromomethyl)benzo[d][1,3]dioxole (0.48 g, 2.21 mmol) according to theprocedure for 99-01. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (q, J=1.2 Hz, 1H),7.81 (dd, J=2.4, 9.6 Hz, 1H), 7.70 (m, 1H), 6.88-6.86 (m, 2H), 6.80 (d,J=8.4 Hz, 1H), 5.95 (s, 2H), 5.61 (s, 1H), 5.49 (s, 1H), 5.19 (s, 2H),3.34 (s, 3H). Mass (m/z): 436.26, [M+H]⁺.

1-(benzo[d][1,3]dioxol-5-ylmethyl)-3-fluoro-5-(2-((3-((2-fluorobenzyl)oxy)-3-phenylpropyl)sulfonyl)-6-(fluoromethyl)pyrimidin-4-yl)pyridin-2(1H)-one(335)

Step 1: The titled compound 335-01 was prepared without purification asa yellow solid (0.6 g) from 334 (0.6 g, 1.38 mmol) according to theprocedure for 140-1. Mass (m/z): 390.30, [M+H]⁺.

Step 2: The title compound 335 (28 mg, 0.042 mmol) was prepared in ayield of 18.3% as a white solid from 335-01(89 mg, 0.23 mmol) and1-((3-chloro-1-phenylpropoxy)methyl)-2-fluorobenzene (83 mg, 0.3 mmol),according to the procedure for 140. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (dd,J=0.8, 2.4 Hz, 1H), 7.80 (dd, J=2.4, 9.6 Hz, 1H), 7.66 (d, J=0.8 Hz,1H), 7.39-7.25 (m, 7H), 7.12 (dt, J=0.8, 7.2 Hz, 1H), 7.03-6.99 (m, 1H),6.86 (m, 1H), 6.84 (d, J=1 Hz, 1H), 6.78-6.76 (m, 1H), 5.95 (s, 2H),5.56 (s, 1H), 5.44 (s, 1H), 5.19 (m, 2H), 4.57 (dd, J=4.8, 8.0 Hz, 1H),4.50 (d, J=12.0 Hz, 1H), 4.36 (d, J=11.6 Hz, 1H), 3.81-3.73 (m, 1H),3.61-3.53 (m, 1H), 2.36-2.21 (m, 2H). Mass (m/z): 664.40, [M+H]⁺.

5-(2-((3-((2-fluorobenzyl)oxy)-3-phenylpropyl)sulfonyl)-6-methylpyrimidin-4-yl)-1-((1-methyl-1H-benzo[d]imidazol-5-yl)methyl)pyridin-2(1H)-oneand5-(2-((3-((2-fluorobenzyl)oxy)-3-phenylpropyl)sulfonyl)-6-methylpyrimidin-4-yl)-1-((1-methyl-1H-benzo[d]imidazol-6-yl)methyl)pyridin-2(1H)-one(336)

Step 1: The title compound 336-01 and 336-01′ (97 mg, 0.14 mmol) wasprepared in a yield of 70% as a white solid from 318-02 (0.1 g, 0.2mmol) and tert-butyl 5-(bromomethyl)-1H-benzo[d]imidazole-1-carboxylate,tert-butyl 6-(bromomethyl)-1H-benzo[d]imidazole-1-carboxylate (81 mg,0.26 mmol), according to the procedure for 85-01. Mass (m/z): 710.49,[M+H]⁺.

Step 2: To a solution of 336-01 and 336-01′(97 mg, 0.14 mmol) in CH₂Cl₂(8 mL) was added TFA (2 mL), which was stirred at r.t for 2 hrs,concentrated the solvent and resolved in ethyl acetate (5 mL) aqueousNaHCO₃ was added to neutralize the acid, separate the organic layer andthe water layer was extracted with ethyl acetate for three times,combined the organic phase, dried and concentrated, the 336-02 was useddirectly without purification. Mass (m/z): 610.47, [M+H]⁺.

Step 3: 336-02 (0.11 g, 0.18 mmol), dimethyl oxalate (32 mg, 0.27 mmol),t-BuOK (30 mg, 0.27 mmol) were dissolved in dry DMF (3 mL), the mixturewas reflux under 150° C. for 3 hrs, then cooled to r.t, concentrated theDMF, and the residue was purified by flash column chromatography(CH₂Cl₂/MeOH 10/1) to give 28 mg (0.045 mmol) of 336-03 and 336-03′ asyellow syrup, yield: 25%. Mass (m/z): 624.49, [M+H]⁺.

Step 4: The title compound 336 (8 mg, 0.012 mmol) was prepared in ayield of 26.7% as a white solid from 336-03 and 336-03′ (28 mg, 0.045mmol) according to the procedure for 99. ¹H NMR (400 Hz, CDCl₃) δ 8.57(s, 1H), 8.49 (s, 1H), 7.82-7.75 (m, 2H), 7.63-7.52 (m, 2H), 7.35-7.29(m, 7H), 7.25-7.21 (m, 1H), 7.09 (t, J=6.4 Hz, 1H), 7.00-6.96 (m, 1H),5.38 (s, 2H), 4.56-4.53 (m, 1H), 4.48 (d, J=11.6 Hz, 1H), 4.36 (d,J=12.0 Hz, 1H), 4.02 (s, 3H), 3.80-3.72 (m, 1H), 3.61-3.54 (m, 1H), 2.56(s, 3H), 2.32-2.24 (m, 2H). Mass (m/z): 656.53, [M+H]⁺.

5-(2-((3-(1H-benzo[d]imidazol-1-yl)propyl)sulfonyl)-6-methylpyrimidin-4-yl)-3-fluoro-1-((1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)methyl)pyridin-2(1H)-one(337)

Step 1: The title compound 337-01 (0.7 g, 2.08 mmol) was prepared in ayield of 63.6% as a white solid from 5-bromo-3-fluoropyridin-2(1H)-one(0.76 g, 3.96 mmol) and6-(bromomethyl)-1-methyl-1H-benzo[d][1,2,3]triazole (0.75 g, 3.3 mmol),according to the procedure for 85-01. Mass (m/z): 337.25, 339.23,[M+H]⁺.

Step 2: The title compound 337-02 (0.5 g, 1.30 mmol) was prepared in ayield of 62.5% as a white solid from 337-01 (0.7 g, 2.08 mmol) accordingto the procedure for 165-01. Mass (m/z): 385.43, [M+H]⁺.

Step 3: The titled compound 337-03 was prepared in a yield of 100% (0.5g, 1.30 mmol) as a white solid from 337-02 (0.5 g, 1.30 mmol) and2,4-dichloro-6-methylpyrimidine (0.32 g, 1.97 mmol) according to theprocedure for 99-01. Mass (m/z): 385.34, [M+H]⁺.

Step 4. The titled compound 337-04 was prepared without purification asa yellow solid (0.43 g) from 337-03 (0.5 g, 1.30 mmol) according to theprocedure for 140-1. Mass (m/z): 383.36, [M+H]⁺.

Step 5: The title compound 337 (10 mg, 0.017 mmol) was prepared in ayield of 18.3% as a white solid from 337-04 (50 mg, 0.13 mmol) and1-(3-bromopropyl)-1H-benzo[d]imidazole (40 mg, 0.17 mmol), according tothe procedure for 140. ¹H NMR (400 Hz, CDCl3) δ 8.61 (s, 1H), 8.27 (m,1H), 7.95-7.93 (m, 1H), 7.76-7.74 (m, 1H), 7.68 (m, 1H), 7.63-7.53 (m,3H), 7.39 (s, 1H), 7.25-7.24 (m, 2H), 5.55 (s, 2H), 4.88-4.86 (m, 2H),4.29 (s, 3H), 3.71 (t, J=5.6 Hz, 2H), 2.70-2.67 (m, 2H), 2.61 (s, 3H).Mass (m/z): 573.68, [M+H]⁺.

5-(2-((3-(1H-benzo[d]imidazol-1-yl)propyl)sulfonyl)-6-methylpyrimidin-4-yl)-1-(benzo[d][1,3]dioxol-5-ylmethyl)-3-fluoropyridin-2(1H)-one(338)

Step 1: The title compound 338-01 (0.48 g, 1.47 mmol) was prepared in ayield of 83.7% as a white solid from 5-bromo-3-fluoropyridin-2(1H)-one(0.41 g, 2.12 mmol) and 5-(bromomethyl)benzo[d][1,3]dioxole (0.38 g,1.77 mmol), according to the procedure for 85-01. Mass (m/z): 326.15,328.15, [M+H]⁺.

Step 2: The title compound 338-02 (0.5 g, 1.34 mmol) was prepared in ayield of 91.2%/as a white solid from 338-01 (0.488 g, 1.47 mmol)according to the procedure for 165-01. Mass (m/z): 374.38, [M+H]⁺.

Step 3. The titled compound 338-03 was prepared in a yield of 53.7%(0.27 g, 0.72 mmol) as a white solid from 338-02 (0.5 g, 1.34 mmol)according to the procedure for 99-01. Mass (m/z): 374.28, [M+H]⁺.

Step 4: The titled compound 338-04 was prepared without purification asa yellow solid (0.3 g) from 338-03 (0.27 g, 0.72 mmol) according to theprocedure for 140-1. Mass (m/z): 372.37, [M+H]⁺.

Step 5: The title compound 338 (25 mg) was prepared in a yield of 34.2%as a white solid from 338-04 (50 mg, 0.13 mmol) and1-(3-bromopropyl)-1H-benzo[d]imidazole (41.6 mg, 0.17 mmol), accordingto the procedure for 140. ¹HNMR (400 MHz, DMSO-d₆) δ 8.78 (m, 1H), 8.34(s, 1H), 8.12 (dd, J=2.4, 11.2 Hz, 1H), 8.07 (s, 1H), 7.65-7.63 (m, 1H),7.57-7.55 (m, 1H), 7.19-7.17 (m, 2H), 7.02 (d, J=1.2 Hz, 1H), 6.91 (dd,J=1.6, 8.0 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 5.97 (s, 2H), 5.19 (s, 2H),4.43 (t, J=6.8 Hz, 2H), 3.72 (m, 2H), 2.52 (s, 3H), 2.27-2.17 (m, 2H).Mass (m/z): 562.59, [M+H]⁺.

Synthesis of Compounds 339-361

Synthesis of Compounds 36, 364, 366

Synthesis of Compounds 363, 365, 367

Synthesis of Compounds 368, 369

Synthesis of Compounds 370-375

Synthesis of Compounds 376-381

Synthesis of Compounds 382

Synthesis of Compounds 383-400

Synthesis of Compounds 401-421

Apoptosis Inhibition Assay

U2OS_Bim cells (a U2OS stable cell line transfected with a Bimtransgene) were cultured in DMEM culture medium (Gibico). On day one,U2OS_Bim cells were plated in 96-well plates at a density of 3000 cellsper well. On day two, cells were pretreated with compounds for one hour.Then cells were treated with 0.1 μg/mL doxycycline (DOX) to triggerapoptosis. 24 hours after DOX treatment, cell viability was determinedby measuring the ATP levels using the Cell Titer-Glo kit (G7570,Promega), according to the manufacturer's instructions. Luminescence wasrecorded with a PerkinElmer EnSpire Multimode Plate Reader. Survivedcells were normalized to those cells treated with DMSO. zVAD (20 μM) wasused as a positive control. Activity data for compounds 1-886 arerepresented as means f standard deviation of duplicates; activity datafor compounds 187-274 are estimated based on preliminary results.

Biological Activity Data, EC 50

Compound EC50 hit 1-10 uM  1 1-10 uM  2 1-10 uM  3 1-10 uM  4 1-10 uM  51-10 uM  6 <100 uM  7 1-10 uM  8 <100 uM  9 1-10 uM  10 1-10 uM  11 1-10uM  12 1-10 uM  13 1-10 uM  14 1-10 uM  15 1-10 uM  16 1-10 uM  17 <100uM  18 1-20 uM  19 1-10 uM  20 1-10 uM  21 <100 uM  22 1-20 uM  23 1-10uM  24 1-10 uM  25 1-10 uM  26 1-10 uM  27 1-10 uM  28 <100 uM  29 1-10uM  30 1-10 uM  31 1-10 uM  32 1-10 uM  33 <100 uM  34 <100 uM  35 1-10uM  36 1-10 uM  37 1-10 uM  38 <100 uM  39 <100 uM  40 <100 uM  41 <100uM  42 <100 uM  43 1-20 uM  44 1-10 uM  45 1-10 uM  46 1-20 uM  47 1-10uM  48 <100 uM  49 <100 uM  50 <100 uM  51 1-10 uM  52 <100 uM  53 <100uM  54 1-20 uM  55 1-20 uM  56 1-20 uM  57 <100 uM  58 <100 uM  59 1-10uM  60 <100 uM  61 <100 uM  62 <100 uM  63 <100 uM  64 <100 uM  65 <100uM  66 1-10 uM  67 <100 uM  68 1-20 uM  69 1-10 uM  70 1-10 uM  71 <100uM  72 1-10 uM  73 1-10 uM  74 <100 uM  75 1-20 uM  76 1-20 uM  77 <100uM  78 <100 uM  79 <100 uM  80 <100 uM  81 <100 uM  82 <100 uM  83 1-10uM  84 1-10 uM  85 1-10 uM  86 <100 uM  87 <100 uM  88 <100 uM  89 <100uM  90 <100 uM  91 <100 uM  92 <100 uM  93 <100 uM  94 <100 uM  95 <100uM  96 <100 uM  97 <100 uM  98 <100 uM  99 <100 uM 100 1-1000 nM 1011-10 uM 102 1-10 uM 103 1-10 uM 104 1-1000 nM 105 1-1000 nM 106 1-1000nM 107 1-1000 nM 108 1-10 uM 109 1-1000 nM 110 1-1000 nM 111 1-1000 nM112 1-1000 nM 113 1-1000 nM 114 1-10 uM 115 1-1000 nM 116 1-10 uM 1171-20 uM 118 1-20 uM 119 1-10 uM 120 1-1000 nM 121 1-1000 nM 122 1-1000nM 123 <100 uM 124 1-1000 nM 125 1-10 uM 126 1-1000 nM 127 1-1000 nM 1281-1000 nM 129 1-1000 nM 130 1-1000 nM 131 1-1000 nM 132 1-1000 nM 1331-10 uM 134 1-10 uM 135 1-1000 nM 136 1-1000 nM 137 1-1000 nM 138 1-1000nM 139 1-10 uM 140 1-1000 nM 141 1-1000 nM 142 1-10 uM 143 1-1000 nM 1441-1000 nM 145 1-1000 nM 146 1-1000 nM 147 1-1000 nM 148 1-1000 nM 1491-1000 nM 150 1-1000 nM 151 1-1000 nM 152 1-1000 nM 153 1-1000 nM 1541-1000 nM 155 1-1000 nM 156 1-1000 nM 157 1-1000 nM 158 <100 uM 159 <100uM 160 1-1000 nM 161 1-1000 nM 162 1-1000 nM 163 1-1000 nM 164 1-1000 nM165 1-1000 nM 166 1-10 uM 167 1-1000 nM 168 1-1000 nM 169 1-1000 nM 1701-1000 nM 171 1-1000 nM 172 1-1000 nM 173 1-10 uM 174 1-1000 nM 1751-1000 nM 176 1-10 uM 177 <100 uM 178 1-1000 nM 179 <100 uM 180 1-1000nM 181 1-1000 nM 182 1-1000 nM 183 1-1000 nM 184 1-1000 nM 185 1-10 uM186 1-1000 nM 187 <10 uM 188 <10 uM 189 <10 uM 190 <10 uM 191 <10 uM 192<10 uM 193 <10 uM 194 <10 uM 195 <10 uM 196 <10 uM 197 <10 uM 198 <10 uM199 <10 uM 200 <10 uM 201 <10 uM 202 <10 uM 203 <10 uM 204 <10 uM 205<10 uM 206 <10 uM 207 <10 uM 208 <10 uM 209 <10 uM 210 <10 uM 211 <10 uM212 <10 uM 213 <10 uM 214 <10 uM 215 <10 uM 216 <10 uM 217 <10 uM 218<10 uM 219 <10 uM 220 <10 uM 221 <10 uM 222 <10 uM 223 <10 uM 224 <10 uM225 <10 uM 226 <10 uM 227 <10 uM 228 <10 uM 229 <10 uM 230 <10 uM 231<10 uM 232 <10 uM 233 <10 uM 234 <10 uM 235 <10 uM 236 <10 uM 237 <10 uM238 <10 uM 239 <10 uM 240 <10 uM 241 <10 uM 242 <10 uM 243 <10 uM 244<10 uM 245 <10 uM 246 <10 uM 247 <10 uM 248 <10 uM 249 <10 uM 250 <10 uM251 <10 uM 252 <10 uM 253 <10 uM 254 <10 uM 255 <10 uM 256 <10 uM 257<10 uM 258 <10 uM 259 <10 uM 260 <10 uM 261 <10 uM 262 <10 uM 263 <10 uM264 <10 uM 265 <10 uM 266 <10 uM 267 <10 uM 268 <10 uM 269 <10 uM 270<10 uM 271 <10 uM

Biological Activity Data, EC 50

Compound EC50 272 1-1000 nM 273 1-10 uM 274 <100 uM 275 <100 uM 2761-1000 nM 277 1-1000 nM 278 1-1000 nM 279 1-1000 nM 280 1-1000 nM 2811-1000 nM 282 1-1000 nM 283 1-1000 nM 284 1-1000 nM 285 1-1000 nM 2861-1000 nM 287 1-1000 nM 288 1-1000 nM 289 1-1000 uM 290 1-10 uM 291 1-10uM 292 1-10 uM 293 1-1000 nM 294 1-1000 nM 295 1-1000 uM 296 1-10 uM 297<100 uM 298 <100 uM 299 <100 uM 300 1-1000 nM 301 1-10 uM 302 1-1000 nM303 <100 uM 304 <100 uM 305 1-1000 nM 307 1-1000 nM 308 <100 uM 309 1-10uM 310 1-10 uM 311 1-1000 nM 312 <100 uM 313 1-10 uM 314 1-1000 nM 315<100 uM 316 1-10 uM 317 1-1000 nM 318 1-1000 nM 319 1-1000 nM 320 1-1000nM 321 1-1000 nM 322 1-1000 nM 323 1-1000 nM 324 1-10 uM 325 1-10 uM 3261-1000 nM 327 1-1000 nM 328 <100 uM 329 1-1000 nM 330 1-1000 nM 3311-1000 nM 332 1-1000 nM 333 1-1000 nM 334 1-10 uM 335 1-1000 nM 3361-1000 nM 337 1-1000 nM* 338 1-1000 nM* 339 1-1000 nM* 340 1-1000 nM*341 1-1000 nM* 342 1-1000 nM* 343 1-1000 nM* 344 1-1000 nM* 345 1-1000nM* 346 1-1000 nM* 347 1-1000 nM* 348 1-1000 nM* 349 1-1000 nM* 3501-1000 nM* 351 1-1000 nM* 352 1-1000 nM* 353 1-1000 nM* 354 1-1000 nM*355 1-1000 nM* 356 1-1000 nM* 357 1-1000 nM* 358 1-1000 nM* 359 1-1000nM* 360 1-1000 nM* 361 1-1000 nM* 362 1-1000 nM* 363 1-1000 nM* 3641-1000 nM* 365 1-1000 nM* 366 1-1000 nM* 367 1-1000 nM* 368 1-1000 nM*369 1-1000 nM* 370 1-1000 nM* 371 1-1000 nM* 372 1-1000 nM* 373 1-1000nM* 374 1-1000 nM* 375 1-1000 nM* 376 1-1000 nM* 377 1-1000 nM* 3781-1000 nM* 379 1-1000 nM* 380 1-1000 nM* 381 1-1000 nM* 382 1-1000 nM*383 1-1000 nM* 384 1-1000 nM* 385 1-1000 nM* 386 1-1000 nM* 387 1-1000nM* 388 1-1000 nM* 389 1-1000 nM* 390 1-1000 nM* 391 1-1000 nM* 3921-1000 nM* 393 1-1000 nM* 394 1-1000 nM* 395 1-1000 nM* 396 1-1000 nM*397 1-1000 nM* 398 1-1000 nM* 399 1-1000 nM* 400 1-1000 nM* 401 1-1000nM* 402 1-1000 nM* 403 1-1000 nM* 404 1-1000 nM* 405 1-1000 nM* 4061-1000 nM* 407 1-1000 nM* 408 1-1000 nM* 409 1-1000 nM* 410 1-1000 nM*411 1-1000 nM* 412 1-1000 nM* 413 1-1000 nM* 414 1-1000 nM* 415 1-1000nM* 416 1-1000 nM* 417 1-1000 nM* 418 1-1000 nM* 419 1-1000 nM* 4201-1000 nM* 421 1-1000 nM* *Est.

1. A sulfonyl or sulfinyl, pyrimidinyl compound of formula I:

or a corresponding or a stereoisomer, hydrate, salt or acetate of saidcompound, wherein: n is 1 or 2; R1 is substituted or unsubstitutedC1-C18 hydrocarbyl, or substituted or unsubstituted C1-C18heterohydrocarbyl; R2 is substituted or unsubstituted heteroatom, orsubstituted or unsubstituted C1-C18 hydrocarbyl, or substituted orunsubstituted C1-C18 heterohydrocarbyl; R3 is substituted5-pyridin-2(1H)-one; and R4 is H or halide.
 2. The method claim 1wherein: R1 is substituted or unsubstituted C1-C18 alkyl or substitutedor unsubstituted C1-C18 heteroalkyl.
 3. The method of claim 1 wherein:R1 is substituted or unsubstituted C1-C4 alkyl.
 4. The method of claim 1wherein: R1 is Me.
 5. The method of claim 1 wherein: R2 is CH₃, F, CH₂F,CHF₂, or CF₃.
 6. The method of claim 1 wherein: R3 is N-substituted withsubstituted or unsubstituted benzyl.
 7. The method of claim 1 wherein:R3 is N-substituted with 3,4-disubstituted benzyl.
 8. The method ofclaim 1 wherein: R3 is 3-substituted with F.
 9. The method of claim 1wherein: R3 is 3-substituted with F, and N-substituted with substitutedor unsubstituted benzyl.
 10. The method of claim 1 wherein: R4 is H. 11.The method claim 1 wherein: R1 is substituted or unsubstituted C1-C18alkyl or substituted or unsubstituted C1-C18 heteroalkyl; R2 is CH₃, F,CH₂F, CHF₂, or CF₃; R3 is N-substituted with substituted orunsubstituted benzyl, and R4 is H.
 12. The method of claim 1 wherein: R1is substituted or unsubstituted C1-C4 alkyl; R2 is CH₃, F, CH₂F, CHF₂,or CF₃, R3 is N-substituted with substituted or unsubstituted benzyl,and R4 is H.
 13. The method of claim 1 wherein: R1 is Me; R2 is CH₃, F,CH₂F, CHF₂, or CF₃, R3 is N-substituted with substituted orunsubstituted benzyl, and R4 is H.
 14. The method of claim 1 wherein:wherein substituents for alkyl and heteroalkyl radicals, as well asthose groups referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl andheterocycloalkenyl, are selected from: —OR′, ═O, ═NR′, ═N—OR′, —NR′R″,—SR′, halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO₂NR′″, —NR″CO₂R′,—NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′, —SO₂R′,—SO₂NR′R″, —NR″SO₂R, —CN and —NO₂, in a number ranging from/zero tothree, wherein R′, R″ and R′″ each independently refer to hydrogen,unsubstituted (C1-C8)alkyl and heteroalkyl, unsubstituted aryl, arylsubstituted with one to three halogens, unsubstituted alkyl, alkoxy orthioalkoxy groups, or aryl-(C1-C4)alkyl groups, wherein when R′ and R″are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 5-, 6- or 7-membered ring; and whereinsubstituents for aryl and heteroaryl groups are selected from: halogen,—OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′, —CONR′R″, —C(O)R′,—OC(O)NR′R″, —NR″C(O)R′, —NR″CO2R′, —NR′—C(O)NR″R′, —NR′—SO₂NR″R′″,—NH—C(NH2)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′, —SO₂R′,—SO₂NR′R″, —NR″SO₂R, —N₃, —CH(Ph)₂, perfluoro(C1-C4)alkoxy andperfluoro(C1-C4)alkyl, in a number ranging from/zero to the total numberof open valences on the aromatic ring system; and where R′, R″ and R′″are independently selected from hydrogen, (C1-C8)alkyl and heteroalkyl,unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C1-C4)alkyl and(unsubstituted aryl)oxy-(C1-C4)alkyl.
 15. The method of claim 14wherein: R3 is N-substituted with substituted or unsubstituted benzyl,wherein substituents for the benzyl are selected from: halogen, —OR′,—OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′, —CONR′R″, —C(O)R′,—OC(O)NR′R″, —NR″C(O)R′, —NR″CO2R′, —NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″,—NH—C(NH2)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′, —SO₂R′,—SO₂NR′R″, —NR″SO₂R, —N₃, —CH(Ph)₂, perfluoro(C1-C4)alkoxy andperfluoro(C1-C4)alkyl, in a number ranging from/zero to the total numberof open valences on the aromatic ring system; and where R′, R″ and R′″are independently selected from hydrogen, (C1-C8)alkyl and heteroalkyl,unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C1-C4)alkyl and(unsubstituted aryl)oxy-(C1-C4)alkyl, and -A-(CH2)r-B—, wherein A and Bare attached to adjacent atoms of the benzyl ring and wherein A and Bare independently —CH₂—, —O—, —NH—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— ora single bond, and r is an integer of from 1 to 3, wherein a single bondof the new ring so formed may be replaced with a double bond, or two ofthe substituents on adjacent atoms of the benzyl ring may be replacedwith a substituent of the formula —(CH₂)s-X—(CH₂)t-, where s and t areindependently integers of from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—,—S(O)₂—, or —S(O)₂NR′—, and the substituent R′ in —NR′— and —S(O)₂NR′—is hydrogen or unsubstituted (C1-C6)alkyl.
 16. The method claim 15wherein: R1 is substituted or unsubstituted C1-C18 alkyl or substitutedor unsubstituted C1-C18 heteroalkyl. R2 is CH₃, F, CH₂F, CHF₂, or CF₃,and R4 is H.
 17. The compound of claim 1 wherein the compound hasstructure selected from Table 4a or 4b.
 18. The compound of claim 1having a structure of Table 4a or 4b.
 19. A pharmaceutical compositioncomprising a compound of claim 1 and a pharmaceutically-acceptableexcipient, in unit dosage form selected from a pill, tablet, capsule, orlozenge.
 20. A method of using the compound of claim 1, the methodcomprising administering the compound to a person in need thereof.